Spiro-substituted azacyclic derivatives and their use as therapeutic agents

ABSTRACT

The present invention relates to compounds of formula (I), wherein n is zero, 1, 2 or 3; R represents C 1-6  alkyl, C 1-6  alkoxy, hydroxy, halogen, cyano, trifluoromethyl SO 2  C 1-6  alkyl, NR a  R b , NR a  COR b  or CONR a  R b , where R a  and R b  are each H, C 1-4  alkyl, phenyl or trifluoromethyl; R 1  represents phenyl optionally substituted by 1, 2 or 3 of C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 3-7  cycloalkyl, C 3-7  cycloalkylC 1-4  alkyl, --O(CH 2 ) p  O-- (where p is 1 or 2), halogen, cyano, nitro, trifluoromethyl, trimethylsilyl, OR a , SR a , SOR a , SO 2  R a , NR a  R b , NR a  COR b , NR a  CO 2  R b , COR a , CO 2  R a  or CONR a  R b  ; naphthyl; benzhydryl; or benyl, where the naphthyl group or each phenyl moiety of benzyl and benzhydryl may be substituted by C 1-6  alkyl, C 1-6  alkoxy, halogen or trifluoromethyl; R 2  represents hydogen, a substituent as defined for R 1  or heteroaryl selected from indazolyl, thienyl, furanyl, pyridyl, thiazolyl, tetrazolyl and quinolinyl; wherein each heteroaryl may be substituted by C 1-6  alkyl, C 1-6  alkoxy, halogen or trifluoromethyl; R 3  and R 4  are each H or C 1-6  alkyl or R 3  and R 4  together are linked so as to form a C 1-3  alkylene chain; R 5  represents H, C 1-6  alkyl, C 3-7  cycloalkyl, C 3-7  cycloalkylC 1-4  alkyl, phenylC 1-4  alkyl, CO 2  R a , CONR a  R b , SOR a  or SO 2  R a , wherein the phenyl moiety may be substituted by C 1-6  alkyl, C 1-6  alkoxy, halogen or trifluoromethyl; X and Y are each H, or together represents ═O; and Z represents a bond, O, S, SO, SO 2 , NR 6 , or --(CR 6  R 6 )-- where R 6  is H or C 1-6  alkyl; or a pharmaceutically acceptable salt thereof. The compounds are of particular use in the treatment or prevention of pain, inflammation, migraine, emesis and postherpetic neuralgia. ##STR1##

This application is 371 of PCT/GB95/08167 which is now published as WO96/05203 on Feb. 22, 1995.

This invention relates to a class of spiro-substituted azacycliccompounds, which are useful as tachykinin antagonists. Moreparticularly, the compounds of the invention comprise an azacyclic ringsystem spiro-substituted by an indolyl moiety and a substituted serinederived moiety.

The tachykinins are a group of naturally occurring peptides found widelydistributed throughout mammalian tissues, both within the centralnervous system and in peripheral nervous and circulatory systems.

At present, there are three known mammalian tachykinins referred to assubstance P, neurokinin A (NKA, substance K, neuromedin L) andneurokinin B (NKB, neuromedin K) (for review see J. E. Maggio, Peptides(1985) 6(suppl. 3), 237-242). The current nomenclature designates thethree tachykinin receptors mediating the biological actions of substanceP, NKA and NKB as the NK₁, NK₂ and NK₃ receptors, respectively.

Evidence for the usefulness of tachykinin receptor antagonists in pain,headache, especially migraine, Alzheimer's disease, multiple sclerosis,attenuation of morphine withdrawal, cardiovascular changes, oedema, suchas oedema caused by thermal injury, chronic inflammatory diseases suchas rheumatoid arthritis, asthma/bronchial hyperreactivity and otherrespiratory diseases including allergic rhinitis, inflammatory diseasesof the gut including ulcerative colitis and Crohn's disease, ocularinjury and ocular inflammatory diseases, proliferativevitreoretinopathy, irritable bowel syndrome and disorders of bladderfunction including cystitis and bladder detruser hyper-reflexia isreviewed in "Tachykinin Receptors and Tachykinin Receptor Antagonists",C. A. Maggi, R. Patacchini, P. Rovero and A. Giachetti, J. Auton.Pharmacol. (1993) 13, 23-93.

For instance, substance P is believed inter alia to be involved in theneurotransmission of pain sensations Otsuka et al, "Role of Substance Pas a Sensory Transmitter in Spinal Cord and Sympathetic Ganglia" in 1982Substance P in the Nervous System, Ciba Foundation Symposium 91, 13-34(published by Pitman) and Otsuka and Yanagisawa, "Does Substance P Actas a Pain Transmitter?" TIPS (1987) 8, 506-510!, specifically in thetransmission of pain in migraine (B. E. B. Sandberg et al, J. Med Chem,(1982) 25, 1009) and in arthritis Levine et al in Science (1984) 226,547-549!. Tachykinins have also been implicated in gastrointestinal (GI)disorders and diseases of the GI tract such as inflammatory boweldisease Mantyh et al in Neuroscience (1988) 25(3), 817-37 and D. Regoliin "Trends in Cluster Headache" Ed. Sicuteri et al Elsevier ScientificPublishers, Amsterdam (1987) page 85)! and emesis F. D. Tattersall etal, Eur. J. Pharmacol., (1993) 250, R⁵ -R⁶ !. It is also hypothesisedthat there is a neurogenic mechanism for arthritis in which substance Pmay play a role Kidd et al "A Neurogenic Mechanism for SymmetricalArthritis" in The Lancet, 11 Nov. 1989 and Gronblad et al,"Neuropeptides in Synovium of Patients with Rheumatoid Arthritis andOsteoarthritis" in J. Rheumatol. (1988) 15(12), 1807-10!. Therefore,substance P is believed to be involved in the inflammatory response indiseases such as rheumatoid arthritis and osteoarthritis, and fibrositisO'Byrne et al, Arthritis and Rheumatism (1990) 33, 1023-8!. Otherdisease areas where tachykinin antagonists are believed to be useful areallergic conditions Hamelet et al, Can. J. Pharmacol. Physiol. (1988)66, 1361-7!, immunoregulation Lotz et al, Science (1988) 241, 1218-21and Kimball et al, J. Immunol. (1988) 141(10), 3564-9! vasodilation,bronchospasm, reflex or neuronal control of the viscera Mantyh et al,PNAS (1988) 85, 3235-9! and, possibly by arresting or slowingβ-amyloid-mediated neurodegenerative changes Yankner et al, Science(1990) 250, 279-82! in senile dementia of the Alzheimer type,Alzheimer's disease and Down's Syndrome.

Tachykinin antagonists may also be useful in the treatment of small cellcarcinomas, in particular small cell lung cancer (SCLC) Langdon et al,Cancer Research (1992) 52, 4554-7!.

Substance P may also play a role in demyelinating diseases such asmultiple sclerosis and amyotrophic lateral sclerosis J. Luber-Narod etal, poster C.I.N.P. XVIIIth Congress, 28th Jun.-2nd Jul. 1992!, and indisorders of bladder function such as bladder detrusor hyper-reflexia(Lancet, 16th May 1992, 1239).

It has furthermore been suggested that tachykinins have utility in thefollowing disorders: depression, dysthymic disorders, chronicobstructive airways disease, hypersensitivity disorders such as poisonivy, vasospastic diseases such as angina and Reynauld's disease,fibrosing and collagen diseases such as scleroderma and eosinophilicfascioliasis, reflex sympathetic dystrophy such as shoulder/handsyndrome, addiction disorders such as alcoholism, stress related somaticdisorders, neuropathy, neuralgia, disorders related to immuneenhancement or suppression such as systemic lupus erythmatosus Europeanpatent specification no. 0 436 334), ophthalmic disease such asconjuctivitis, vernal conjunctivitis, and the like, and cutaneousdiseases such as contact dermatitis, atopic dermatitis, urticaria, andother eczematoid dermatitis (European patent specification no. 0 394989).

In view of their metabolic instability, peptide derivatives are likelyto be of limited utility as therapeutic agents. It is for this reasonthat non-peptide tachykinin antagonists are sought.

In essence, this invention provides a class of potent non-peptidetachykinin antagonists.

The present invention provides a compound of formula (I), or apharmaceutically acceptable salt thereof: ##STR2## wherein n is zero, 1,2 or 3;

R represents C₁₋₆ alkyl, C₁₋₆ alkoxy, hydroxy, halogen, cyano,trifluoromethyl, SO₂ C₁₋₆ alkyl, NR^(a) R^(b), NR^(a) COR^(b), orCONR^(a) R^(b), where R^(a) and R^(b) each independently representhydrogen, C₁₋₆ alkyl, phenyl or trifluoromethyl;

R¹ represents unsubstituted phenyl or phenyl substituted by 1, 2 or 3groups selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇cycloalkyl, C₃₋₇ cycloalkylC₁₋₄ alkyl, --O(CH₂)_(p) O-- where p is 1 or2, halogen, cyano, nitro, trifluoromethyl, trimethylsilyl, OR^(a),SR^(a), SOR^(a), SO₂ R^(a), NR^(a) R^(b), NR^(a) COR^(b), NR^(a) CO₂R^(b), COR^(a), CO₂ R^(a) or CONR^(a) R^(b), where R^(a) and R^(b) areas previously defined; naphthyl; benzhydryl; or benzyl, where thenaphthyl group or each phenyl moiety of benzyl and benzhydryl may besubstituted by C₁₋₆ alkyl, C₁₋₆ alkoxy, halogen or trifluoromethyl;

R² represents hydrogen; unsubstituted phenyl or phenyl substituted by 1,2 or 3 groups selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇cycloalkyl, C₃₋₇ cycloalkylC₁₋₄ alkyl, --O(CH₂)_(p) O-- where p is 1 or2, halogen, cyano, nitro, trifluoromethyl, trimethylsilyl, OR^(a),SR^(a), SOR^(a), SO₂ R^(a), NR^(a) R^(b), NR^(a) COR^(b), NR^(a) CO₂R^(b), COR^(a), CO₂ R^(a), or CONR^(a) R^(b), where R^(a) and R^(b) areas previously defined; heteroaryl selected from indazolyl, thienyl,furanyl, pyridyl, thiazolyl, tetrazolyl and quinolinyl; naphthyl;benzhydryl; or benzyl; wherein each heteroaryl, the naphthyl group andeach phenyl moiety of benzyl and benzhydryl may be substituted by C₁₋₆alkyl, C₁₋₆ alkoxy, halogen or trifluoromethyl;

R³ and R⁴ each independently represents hydrogen or C₁₋₆ alkyl or R³ andR⁴ together are linked so as to form a C₁₋₃ alkylene chain;

R⁵ represents hydrogen, C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkylC₁₋₄alkyl, phenylC₁₋₄ alkyl, CO₂ R^(a), CONR^(a) R^(b), SOR^(a) or SO₂R^(a), wherein the phenyl moiety may be substituted by C₁₋₆ alkyl, C₁₋₆alkoxy, halogen or trifluoromethyl, and R^(a) and R^(b) are aspreviously defined;

X and Y each independently represents hydrogen, or together form a group═O; and

Z represents a bond, O, S, SO, SO₂, NR⁶, or --(CR⁶ R⁶)-- where each R⁶is hydrogen or C₁₋₆ alkyl.

As used herein, the definition of each expression, when it occurs morethan once in any structure, is intended to be independent of itsdefinition elsewhere in the same structure.

The alkyl, alkenyl and alkynyl groups referred to with respect to theformulae herein may represent straight or branched groups. Thus, forexample, suitable alkyl groups include methyl, ethyl, n- or iso-propyland n-, sec-, iso- or tert-butyl. The cycloalkyl groups referred toabove may be, for example, cyclopropyl, cyclobutyl, cyclopentyl orcyclohexyl. Similarly, suitable cycloalkylalkyl groups includecyclopropylmethyl. Suitable alkenyl groups include vinyl and allyl; andsuitable alkynyl groups include propargyl.

The term "halogen" as used herein includes fluorine, chlorine, bromineand iodine, especially chlorine and fluorine.

The present invention includes within its scope prodrugs of thecompounds of formula (1) above. In general, such prodrugs will befunctional derivatives of the compounds of formula (I) which are readilyconvertible in vivo into the required compound of formula (I).Conventional procedures for the selection and preparation of suitableprodrug derivatives are described, for example, in "Design of Prodrugs",ed. H. Bundgaard, Elsevier, 1985.

Those compounds according to the invention which contain one or morechiral centres may exist both as enantiomers and as diastereomers. It isto be understood that all such isomers and mixtures thereof areencompassed within the scope of the present invention.

Preferably n is zero.

Preferably R¹ represents unsubstituted phenyl or phenyl substituted byone or two groups selected from C₁₋₆ alkyl such as methyl, halogen suchas chlorine, fluorine and bromine, and trifluoromethyl. Particularlypreferred substituents are chlorine and trifluoromethyl.

Most preferably, R¹ represents disubstituted phenyl, in particular3,4-disubstituted phenyl, especially 3,4-dichlorophenyl.

Suitable values for the group R² include unsubstituted or substitutedphenyl, 5-membered heteroaryl such as thienyl or furanyl, 6-memberedheteroaryl such as pyridyl, quinolinyl, naphthyl, and benzhydryl.

Preferably R² represents unsubstituted or substituted phenyl, especiallyunsubstituted phenyl.

When R² represents substituted phenyl it preferably representsdichlorophenyl, especially 3,4-dichlorophenyl.

Preferably R³ and R⁴ each independently represent hydrogen.

Preferably R⁵ represents the group SO₂ R^(a) where R^(a) is aspreviously defined. Particularly preferred is the group SO₂ (C₁₋₆alkyl), especially SO₂ CH₃.

Preferably X and Y are both hydrogen atoms.

Preferably Z is an oxygen atom.

In another preferred class of compounds of formula (I), Z is preferably--CH₂ --.

A particular sub-class of compounds according to the invention isrepresented by compounds of formula (Ia), and pharmaceuticallyacceptable salts thereof. ##STR3## wherein X and Y are as defined forformula (I);

Z' is O, S or --CH₂ --, especially O or S;

R²⁰ and R²¹ independently represent hydrogen, C₁₋₆ alkyl, halogen,trifluoromethyl, OR^(a), or NR^(a) R^(b), where R^(a) and R^(b) are aspreviously defined; and

R²² and R²³ independently represent hydrogen or halogen, preferablyhydrogen or chlorine.

Particular values of R²⁰ and R²¹ include hydrogen, chlorine, fluorine,methyl, trifluoromethyl, methoxy and dimethylamino.

Another preferred sub-class of compounds according to the invention isrepresented by compounds of formula (Ib), and pharmaceuticallyacceptable salts thereof: ##STR4## wherein Z" is O or --CH₂ --,especially O;

R²⁴ and R²⁵ independently represent hydrogen or chlorine; and

R²⁶ and R²⁷ independently represent hydrogen or chlorine, with theproviso that at least one of R²⁶ and R²⁷ represents chlorine.

Specific compounds within the scope of the present invention include:

N-1-methanesulphonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-(3,4-dichlorobenzamido)propionamide;

N-1-methanesulphonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-(3-pyridylcarboxamido)propionamide;

N-1-methanesulphonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-(2-chlorobenzamido)propionamide;

N-1-methanesulphonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-(3-chlorobenzamido)propionamide;

N-1-methanesulphonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-(4-chlorobenzamido)propionamide;

N-1-methanesulphonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-(2,6-dichlorobenzamido)propionamide;

N-1-methanesulphonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-(3,5-dichlorobenzamido)propionamide;

N-1-methanesulphonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-(2,5-dichlorobenzamido)propionamide;

N-1-methanesulphonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-(2,4-dichlorobenzamido)propionamide;

N-1-methanesulphonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-(2,3-dichlorobenzamido)propionamide;

N-1-methanesulphonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-(3,4-dimethoxybenzamido)propionamide;

N-1-methanesulphonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-benzamidopropionamide;

N-1-methanesulphonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-(3-(2-propyloxy)benzamido)propionamide;

N-1-methanesulphonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-(1-naphthyl)carboxamido)!propionamide;

N-1-methanesulphonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-(2-naphthyl)carboxamido)!propionamide;

N-1-methanesulphonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-(phenylacetamido)propionamide;

N-1-methanesulphonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-(3,4-dichlorophenylacetamido)propionamide;

N-1-methanesulphonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-(3,5-bis(trifluoromethyl)phenyl)acetamido!propionamide;

N-1-methanesulphonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-(diphenylacetamido)propionamide;

N-1-methanesulphonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-(4-pyridylcarboxamido)propionamide;

N-1-methanesulphonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-(2-pyridylcarboxamido)propionamide;

N-1-methanesulphonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-(8-quinolinylcarboxamido)propionamide;

and pharmaceutically acceptable salts thereof

Particularly preferred compounds within the scope of the presentinvention include:

N-1-methanesulphonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-(3,4-dichlorobenzylamino)propionamide;

N-1-methanesulphonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-(2-methoxybenzylamino)propionamide;

N-1-methanesulphonylspiro(3H-indole-3,4'-piperidin)-1-yl!-2-benzylamino-3-benzyloxypropionamide;

N-1-methanesulphonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-(2-chlorobenzylamino)propionamide;

N-1-methanesulphonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-(3-chlorobenzylamino)propionamide;

N-1-methanesulphonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-(4-chlorobenzylamino)propionamide;

N-1-methanesulphonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-(3-bromobenzylamino)propionamide;

N-1-methanesulphonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-(3-fluorobenzylamino)propionamide;

N-1-methanesulphonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-(3-cyanobenzylamino)propionamide;

N-1-methanesulphonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-(3-nitrobenzylamino)propionamide;

N-1-methanesulphonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-(3-methylbenzylamino)propionamide;

N-1-methanesulphonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-(3-methoxybenzylamino)propionamide;

N-1-methanesulphonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-(4-methoxybenzylamino)propionamide;

N-1-methanesulphonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-(4-(dimethylamino)benzylamino)propionamide;

N-1-methanesulphonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-(2,4-dichlorobenzylamino)propionamide;

N-1-methanesulphonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-(3,5-dichlorobenzylamino)propionamide;

N-1-methanesulphonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-(2,3-dichlorobenzylamino)propionamide;

N-1-methanesulphonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-(2,6-dichlorobenzylamino)propionamide;

N-1-methanesulphonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-(3,5-dimethoxybenzylamino)propionamide;

N-1-methanesulphonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-(3-chloro-5-methoxybenzylamino)propionamide;

N-1-methanesulphonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-(3,4-dimethoxybenzylamino)propionamide;

N-1-methanesulphonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-(3,4-methylenedioxybenzylamino)propionamide;

N-1-methanesulphonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-(1-naphthylmethylamino)propionamide;

N-1-methanesulphonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-(2-naphthylmethylamino)propionamide;

N-1-methanesulphonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-(2-pyridylmethylamino)propionamide;

N-1-methanesulphonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-(3-pyridylmethylamino)propionamide;

N-1-methanesulphonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-(4-pyridylmethylamino)propionamide;

N-1-methanesulphonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-(2-furylmethylamino)propionamide;

N-1-methanesulphonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-(5-methylfur-2-yl)methylamino!propionamide;

N-1-methanesulphonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-(3-methylthiophen-2-yl)methylamino!propionamide;

N-1-methanesulphonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-(5-methylthiophen-2-yl)methylamino!propionamide;

N-1-methanesulphonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-(N-(3,4-dichlorobenzyl)-N-(methyl)amino)propionamide;

N-1-methanesulphonylspiro(3H-indole-3,4'-piperidin)-1-yl!-2-benzylamino-3-(2-chlorobenzyloxy)propionamide;

N-1-methanesulphonylspiro(3H-indole-3,4'-piperidin)-1-yl!-2-benzylamino-3-(3-chlorobenzyloxy)propionamide;

N-1-methanesulphonylspiro(3H-indole-3,4'-piperidin)-1-yl!-2-benzylamino-3-(4-chlorobenzyloxy)propionamide;

N-1-methanesulphonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-(2-chlorobenzyloxy)-2-(3,4-dichlorobenzylamino)propionamide;

N-1-methanesulphonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-(3-chlorobenzyloxy)-2-(3,4-dichlorobenzylamino)propionamide;

N-1-methanesulphonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-(4-chlorobenzyloxy)-2-(3,4-dichlorobenzylamino)propionamide;

N-1-methanesulphonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-(benzylthio)-2-(3,4-dichlorobenzylamino)propionamide;

N-1-methanesulphonylspiro(3H-indole-3,4'-piperidin)-1-yl!-2-benzylamino-3-(3,4-dichlorobenzyloxy)propionamide;

N-1-methanesulphonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-(3,4-dichlorobenzyloxy)-2-(3,4-dichlorobenzylamino)propionamide;

and pharmaceutically acceptable salts thereof.

Further preferred compounds of the present invention include:

N-1-methanesulfonylspiro(3H-indole-3,4'-piperidin)-1-yl!-2-(benzylamino)-3-(napth-2-yl)methoxy!propionamide;

N-1-methanesulfonylspiro(3H-indole-3,4'-piperidin)-1-yl!-2-(benzylamino)-3-(napth-1-yl)methoxy!propionamide;

N- 1-methanesulfonylspiro(3H-indole-3,4'-piperidin)-1-yl!-2-N-(methyl)benzylamino!-3-(3,4-dichlorobenzyloxy)propionamide;

N-1-methanesulfonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-(3,4-dichlorobenzyloxy)-2-(dimethyl)aminopropionamide;

N-1-methanesulfonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-(3,4-dichlorobenzylthio)-2-(benzylamino)propionamide;

N-1-methanesulfonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-(3,4-dichlorobenzylsulfonyl)-2-(benzylamino)propionamide;

N-1-methanesulfonylspiro(3H-indole-3,4'-piperidin)-1-yl!-2,3-bis(benzylamino)propionamide;

N-1-methanesulfonylspiro(3H-indole-3,4'-piperidin)-1-yl!-2-(benzylamino)-3-(3,4-dichlorobenzylamino)propionamide;

N-1-methanesulfonylspiro(3H-indole-3,4'-piperidin)-1-yl!-2-(benzylamino)-3-(N-methyl-3,4-dichlorobenzylamino)propionamide;

N-1-methanesulfonylspiro(3H-indole-3,4'-piperidin)-1-yl!-2-(benzylamino)-5-phenylpentanamide;

N-1-methanesulfonylspiro(3H-indole-3,4'-piperidin)-1-yl!-2-(benzylamino)-5-(3,4-dichlorophenyl)pentanamide;

N-1-methanesulfonylspiro(3H-indole-3,4'-piperidin)-1-yl!-2-(benzylamino)-5-(3,4-dichlorophenyl)butanamide;

and pharmaceutically acceptable salts thereof

Especially preferred compounds of the present invention include:

N-1-methanesulfonylspiro(3H-indole-3,4'-piperidin)-1-yl!-2-(benzylamino)-3-(3,4-dichlorobenzyloxy)propionamide;

N-1-methanesulfonylspiro(3H-indole-3,4'-piperidin)-1-yl!-2-(3,4-dichlorobenzylamino)-3-(3,4-dichlorobenzyloxy)propionaamide;

and pharmaceutically acceptable salts thereof.

For use in medicine, the salts of the compounds of formula (I) will bepharmaceutically acceptable salts. Other salts may, however, be usefulin the preparation of the compounds according to the invention (such asthe dibenzoyltartrate salts) or of their pharmaceutically acceptablesalts. Suitable pharmaceutically acceptable salts of the compounds ofthis invention include acid addition salts which may, for example, beformed by mixing a solution of the compound according to the inventionwith a solution of a pharmaceutically acceptable non-toxic acid such ashydrochloric acid, sulphuric acid, fumaric acid, maleic acid, succinicacid, acetic acid, citric acid, tartaric acid, carbonic acid, phosphoricacid or p-toluenesulphonic acid. Salts of amine groups may also comprisequaternary ammonium salts in which the amino nitrogen atom carries asuitable organic group such as an alkyl, alkenyl, alkynyl or aralkylmoiety. Furthermore, where the compounds of the invention carry anacidic moiety, suitable pharmaceutically acceptable salts thereof mayinclude metal salts such as alkali metal salts, e.g. sodium or potassiumsalts; and alkaline earth metal salts, e.g. calcium or magnesium salts.

Preferred salts of the compounds according to the invention include thehydrochloride and p-toluenesulphonic acid salts.

The invention also provides pharmaceutical compositions comprising oneor more compounds of this invention in association with apharmaceutically acceptable carrier. Preferably these compositions arein unit dosage forms such as tablets, pills, capsules, powders,granules, solutions or suspensions, or suppositories, for oral,parenteral or rectal administration, or topical administration includingadministration by inhalation or insufflation.

The invention further provides a process for the preparation of apharmaceutical composition comprising a compound of formula (I), or asalt or prodrug thereof, and a pharmaceutically acceptable carrier,which process comprises bringing a compound of formula (I), or a salt orprodrug thereof into association with a pharmaceutically acceptablecarrier.

For preparing solid compositions such as tablets, the principal activeingredient is mixed with a pharmaceutical carrier, e.g. conventionaltableting ingredients such as corn starch, lactose, sucrose, sorbitol,talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, andother pharmaceutical diluents, e.g. water, to form a solidpreformulation composition containing a homogeneous mixture of acompound of the present invention, or a non-toxic pharmaceuticallyacceptable salt thereof. When referring to these preformulationcompositions as homogeneous, it is meant that the active ingredient isdispersed evenly throughout the composition so that the composition maybe readily subdivided into equally effective unit dosage forms such astablets, pills and capsules. This solid preformulation composition isthen subdivided into unit dosage forms of the type described abovecontaining from 0.1 to about 500 mg of the active ingredient of thepresent invention. The tablets or pills of the novel composition can becoated or otherwise compounded to provide a dosage. form affording theadvantage of prolonged action. For example, the tablet or pill cancomprise an inner dosage and an outer dosage component, the latter beingin the form of an envelope over the former. The two components can beseparated by an enteric layer which serves to resist disintegration inthe stomach and permits the inner component to pass intact into theduodenum or to be delayed in release. A variety of materials can be usedfor such enteric layers or coatings, such materials including a numberof polymeric acids and mixtures of polymeric acids with such materialsas shellac, cetyl alcohol and cellulose acetate.

The liquid forms in which the novel compositions of the presentinvention may be incorporated for administration orally or by injectioninclude aqueous solutions, suitably flavoured syrups, aqueous or oilsuspensions, and flavoured emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles. Suitable dispersing or suspendingagents for aqueous suspensions include synthetic and natural gums suchas tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose,methylcellulose, polyvinyl-pyrrolidone or gelatin.

Preferred compositions for administration by injection include thosecomprising a compound of formula (I), as the active ingredient, inassociation with a surface-active agent (or wetting agent or surfactant)or in the form of an emulsion (as a water-in-oil or oil-in-wateremulsion).

Suitable surface-active agents include, in particular, non-ionic agents,such as polyoxyethylenesorbitans (e.g. Tween™ 20, 40, 60, 80 or 85) andother sorbitans (e.g. Span™ 20, 40, 60, 80 or 85). Compositions with asurface-active agent will conveniently comprise between 0.05 and 5%surface-active agent, and preferably between 0.1 and 2.5%. It will beappreciated that other ingredients may be added, for example mannitol orother pharmaceutically acceptable vehicles, if necessary.

Suitable emulsions may be prepared using commercially available fatemulsions, such as Intralipid™, Liposyn™, Infonutrol™, Lipofundin™ andLipiphysan™. The active ingredient may be either dissolved in a premixedemulsion composition or alternatively it may be dissolved in an oil(e.g. soybean oil, safflower oil, cottonseed oil, sesame oil, corn oilor almond oil) and an emulsion formed upon mixing with a phospholipid(e.g. egg phospholipids, soybean phospholipids or soybean lecithin) andwater. It will be appreciated that other ingredients may be added, forexample gylcerol or glucose, to adjust the tonicity of the emulsion.Suitable emulsions will typically contain up to 20% oil, for example,between 5 and 20%. The fat emulsion will preferably comprise fatdroplets between 0.1 and 1.0 μm, particularly 0.1 and 0.5 μm, and have apH in the range of 5.5 to 8.0.

Particularly preferred emulsion compositions are those prepared bymixing a compound of formula (I) with Intralipid™ or the componentsthereof (soybean oil, egg phospholipids, glycerol and water).

Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as set outabove. Preferably the compositions are administered by the oral or nasalrespiratory route for local or systemic effect. Compositions inpreferably sterile pharmaceutically acceptable solvents may be nebulisedby use of inert gases. Nebulised solutions may be breathed directly fromthe nebulising device or the nebulising device may be attached to a facemask, tent or intermittent positive pressure breathing machine.Solution, suspension or powder compositions may be administered,preferably orally or nasally, from devices which deliver the formulationin an appropriate manner.

The present invention further provides a process for the preparation ofa pharmaceutical composition comprising a compound of formula (I), whichprocess comprises bringing a compound of formula (I) into associationwith a pharmaceutically acceptable carrier or excipient.

The compounds of formula (I) are of value in the treatment of a widevariety of clinical conditions which are characterised by the presenceof an excess of tachykinin, in particular substance P, activity. Thesemay include disorders of the central nervous system such as anxiety,depression, psychosis and schizophrenia; epilepsy; neurodegenerativedisorders such as dementia, including AIDS related dementia, seniledementia of the Alzheimer type, Alzheimer's disease and Down's syndrome;demyelinating diseases such as multiple sclerosis OS) and amyotrophiclateral sclerosis (ALS; Lou Gehrig's disease) and otherneuropathological disorders such as peripheral neuropathy, for exampleAIDS related neuropathy, diabetic and chemotherapy-induced neuropathy,and postherpetic and other neuralgias; neuronal damage, such ascerebralischemic damage and cerebral edema in cerebrovascular disorders;small cell carcinomas such as small cell lung cancer; respiratorydiseases, particularly those associated with excess mucus secretion suchas chronic obstructive airways disease, bronchopneumonia, chronicbronchitis, asthma, and bronchospasm; airways diseases modulated byneurogenic inflammation; diseases characterised by neurogenic mucussecretion, such as cystic fibrosis; diseases associated with decreasedglandular secretions, including lacrimation, such as Sjogren's syndrome,hyperlipoproteinemias IV and V, hemocromatosis, sarcoidosis, andamyloidosis; inflammatory diseases such as inflammatory bowel disease,psoriasis, fibrositis, ocular inflammation, osteoarthritis, rheumatoidarthritis, pruritis and sunburn; allergies such as eczema and rhinitis;hypersensitivity disorders such as poison ivy; ophthalmic diseases suchas conjunctivitis, vernal conjunctivitis, dry eye syndrome, and thelike; ophthalmic conditions associated with cell proliferation such asproliferative vitreoretinopathy; cutaneous diseases such as contactdermatitis, atopic dermatitis, urticaria, and other eczematoiddermatitis;

addiction disorders including the withdrawal response produced bychronic treatment with, or abuse of, drugs such as benzodiazepines,opiates, cocaine, alcohol and nicotine; stress related somaticdisorders; reflex sympathetic dystrophy such as shoulder/hand syndrome;dysthymic disorders; adverse immunological reactions such as rejectionof transplanted tissues and disorders related to immune enhancement orsuppression such as systemic lupus erythematosus; gastrointestinal (GI)disorders, including inflammatory disorders and diseases of the GI tractsuch as gastritis, gastroduodenal ulcers, gastric carcinomas, gastriclymphomas, disorders associated with the neuronal control of viscera,ulcerative colitis, Crohn's disease, irritable bowel syndrome andemesis, including acute, delayed, post-operative, late phase oranticipatory emesis such as emesis induced by chemotherapy, radiation,toxins, viral or bacterial infections, pregnancy, vestibular disorders,motion, surgery, migraine, opioid analgesics, and variations inintercranial pressure, in particular, for example, drug or radiationinduced emesis or post-operative nausea and vomiting; disorders ofbladder function such as cystitis, bladder detrusor hyper-reflexia andincontinence; fibrosing and collagen diseases such as scleroderma andeosinophilic fascioliasis; disorders of blood flow caused byvasodilation and vasospastic diseases such as angina, migraine andReynaud's disease; and pain or nociception, for example, thatattributable to or associated with any of the foregoing conditions,especially the transmission of pain in migraine.

Hence, the compounds of the present invention may be of use in thetreatment of physiological disorders associated with excessivestimulation of tachykinin receptors, especially neurokinin-1 receptors,and as neurokinin-1 antagonists for the control and/or treatment of anyof the aforementioned clinical conditions in mammals, including humans.

The compounds of formula (I) are also of value in the treatment of acombination of the above conditions, in particular in the treatment ofcombined post-operative pain and post-operative nausea and vomiting.

The compounds of formula (I) are particularly useful in the. treatmentof emesis, including acute, delayed, post-operative, late phase oranticipatory emesis, such as emesis or nausea induced by chemotherapy,radiation, toxins, such as metabolic or microbial toxins, viral orbacterial infections, pregnancy, vestibular disorders, motion,mechanical stimulation, gastrointestinal obstruction, reducedgatrointestinal motility, visceral pain, psychological stress ordisturbance, high altitude, weightlessness, opioid analgesics,intoxication, resulting for example from consumption of alcohol,surgery, migraine, and variations in intercranial pressure. Mostespecially, the compounds of formula (I) are of use in the treatment ofemesis induced by antineoplastic (cytotoxic) agents including thoseroutinely used in cancer chemotherapy.

Examples of such chemotherapeutic agents include alkylating agents, forexample, nitrogen mustards, ethyleneimine compounds, alkyl sulphonatesand other compounds with an alkylating action such as nitrosoureas,cisplatin and dacarbazine; antimetabolites, for example, folic acid,purine or pyrimidine antagonists; mitotic inhibitors, for example, vincaalkaloids and derivatives of podophyllotoxin; and cytotoxic antibiotics.

Particular examples of chemotherapeutic agents are described, forinstance, by D. J. Stewart in "Nausea and Vomiting: Recent Research andClinical Advances", Eds. J. Kuucharczyk et al, CRC Press Inc., BocaRaton, Fla., U.S.A. (1991) pages 177-203, especially page 188. Commonlyused chemotherapeutic agents include cisplatin, dacarbazine (DTIC),dactinomycin, mechlorethamine (nitrogen mustard), streptozocin,cyclophosphamide, carmustine (BCNU), lomustine (CCNU), doxorubicin(adriamycin), daunorubicin, procarbazine, mitomycin, cytarabine,etoposide, methotrexate, 5-fluorouracil, vinblastine, vincristine,bleomycin and chlorambucil R. J. Gralla et al in Cancer TreatmentReports (1984) 68(1), 163-172!.

The compounds of formula (I) are also of use in the treatment of emesisinduced by radiation including radiation therapy such as in thetreatment of cancer, or radiation sickness; and in the treatment ofpost-operative nausea and vomiting.

It will be appreciated that the compounds of formula (I) may bepresented together with another therapeutic agent as a combinedpreparation for simultaneous, separate or sequential use for the reliefof emesis. Such combined preparations may be, for example, in the formof a twin pack.

A further aspect of the present invention comprises the compounds offormula (I) in combination with a 5-HT₃ antagonist, such as ondansetron,granisetron or tropisetron, or other anti-emetic medicaments, forexample, a dopamine antagonist such as metoclopramide or GABA_(B)receptor agonists such as baclofen. Additionally, a compound of formula(I) may be administered in combination with an anti-inflammatorycorticosteroid, such as dexamethasone, triamcinolone, triamcinoloneacetonide, flunisolide, budesonide, or others such as those disclosed inU.S. Pat. Nos. 2,789,118, 2,990,401, 3,048,581, 3,126,375, 3,929,768,3,996,359, 3,928,326 and 3,749,712. Dexamethasone (Decadron™) isparticularly preferred. Furthermore, a compound of formula (I) may beadministered in combination with a chemotherapeutic agent such as analkylating agent, antimetabolite, mitotic inhibitor or cytotoxicantibiotic, as described above. In general, the currently availabledosage forms of the known therapeutic agents for use in suchcombinations will be suitable.

When tested in the ferret model of cisplatin-induced emesis described byF. D. Tattersall et al, in Eur. J. pharmacol., (1993) 250, R5-R6, thecompounds of the present invention were found to attenuate the retchingand vomiting induced by cisplatin.

The compounds of formula (I) are also particularly useful in thetreatment of pain or nociception and/or inflammation and disordersassociated therewith such as, for example, neuropathy, such as-diabeticand chemotherapy-induced neuropathy, postherpetic and other neuralgias,asthma, osteroarthritis, rheumatoid arthritis, headache and especiallymigraine.

The present invention further provides a compound of formula (I) for usein therapy.

According to a further or alternative aspect, the present inventionprovides a compound of formula (I) for use in the manufacture of amedicament for the treatment of physiological disorders associated withan excess of tachykinins, especially substance P.

The present invention also provides a method for the the treatment orprevention of physiological disorders associated with an excess oftachykinins, especially substance P, which method comprisesadministration to a patient in need thereof of a tachykinin reducingamount of a compound of formula (I) or a composition comprising acompound of formula (I).

For the treatment of certain conditions it may be desirable to employ acompound according to the present invention in conjunction with anotherpharmacologically active agent. For example, for the treatment ofrespiratory diseases such as asthma, a compound of formula (I) may beused in conjunction with a bronchodilator, such as a β₂ -adrenergicreceptor antagonist or tachykinin antagonist which acts at NK-2receptors. The compound of formula (I) and the bronchodilator may beadministered to a patient simultaneously, sequentially or incombination.

Likewise, a compound of the present invention may be employed with aleukotriene antagonists, such as a leukotriene D₄ antagonist such as acompound selected from those disclosed in European patent specificationnos. 0 480 717 and 0 604 114 and in U.S. Pat. Nos. 4,859,692 and5,270,324. This combination is particularly useful in the treatment ofrespiratory diseases such as asthma, chronic bronchitis and cough.

The present invention accordingly provides a method for the treatment ofa respiratory disease, such as asthma, which method comprisesadministration to a patient in need thereof of an effective amount of acompound of formula (I) and an effective amount of a bronchodilator.

The present invention also provides a composition comprising a compoundof formula (I), a bronchodilator, and a pharmaceutically acceptablecarrier.

It will be appreciated that for the treatment or prevention of migraine,a compound of the present invention may be used in conjunction withother anti-migraine agents, such as ergotamines or 5-HT₁ agonists,especially sumatriptan.

Likewise, for the treatment of behavioural hyperalgesia, a compound ofthe present invention may be used in conjunction with an antagonist ofN-methyl D-aspartate (NMDA), such as dizocilpine.

For the treatment or prevention of inflammatory conditions in the lowerurinary tract, especially cystitis, a compound of the present inventionmay be used in conjunction with an antiinflammatory agent such as abradykinin receptor antagonist.

In the treatment of the conditions associated with an excess oftachykinins, a suitable dosage level is about 0.001 to 50 mg/kg per day,in particular about 0.01 to about 25 mg/kg, such as from about 0.05 toabout mg/kg per day.

For example, in the treatment of conditions involving theneurotransmission of pain sensations, a suitable dosage level is about0.001 to 25 mg/kg per day, preferably about 0.005 to 10 mg/kg per day,and especially about 0.005 to 5 mg/kg per day. The compounds may beadministered on a regimen of 1 to 4 times per day, preferably once ortwice per day.

In the treatment of emesis using an injectable formulation, a suitabledosage level is about 0.001 to 10 mg/kg per day, preferably about 0.005to 5 mg/kg per day, and especially 0.01 to 1 mg/kg per day. Thecompounds may be administered on a regimen of 1 to 4 times per day,preferably once or twice per day.

It will be appreciated that the amount of a compound of formula (I)required for use in any treatment will vary not only with the particularcompounds or composition selected but also with the route ofadministration, the nature of the condition being treated, and the ageand condition of the patient, and will ultimately be at the discretionof the attendant physician.

According to process (A), compounds of formula (I) wherein X and Y areboth hydrogen, may be prepared from compounds of formula (II): ##STR5##wherein R, R¹, R³, R⁴, R⁵, Z and n are as defined for formula (I), byreaction with an aldehyde of formula R² --CHO in the presence of areducing agent.

Suitable reducing agents of use in the reaction include hydride reducingagents such as sodium cyanoborohydride or sodium borohydride.

The reaction is conveniently effected in a suitable solvent such asdimethylformamide or dichloromethane, conveniently at room temperature.

According to a process (B), compounds of formula (I) wherein X and Ytogether form a group ═O, may be prepared by the reaction of a compoundof formula (II) with an acyl halide of formula R² --COHal where Hal is ahalogen atom. typically chlorine, fluorine or bromine, especiallychlorine.

The reaction is conveniently effected in the presence of an acylationcatalyst such as 4-dimethylaminopyridine in a suitable solvent such asdichloromethane at a temperature between -10° C. and 40° C.,conveniently at room temperature.

According to a further process (C), compounds of formula (I) may beprepared by the reaction of a compound of formula (III) with apiperidinyl derivative of formula (IV): ##STR6## wherein R, R¹, R², R³,R⁴, R⁵, X, Y, Z and n are as defined for formula (I) with the provisothat R⁵ is not hydrogen.

The reaction is effected in the presence of a suitable coupling agent,such as dicyclocarbonyldiimide, N,N'-carbonyldiimide or1-(3-dimethylaminopropyl)-3-ethylcarbodiimide optionally in the presenceof an additive such as 1-hydroxybenzotriazole.

The reaction is conveniently effected in a suitable solvent such asdimethylformamide, conveniently at room temperature.

Further useful synthetic methods are those commonly used in standardsyntheses of amino acids, for example, as described in Chemistry andBiochemistry of the Amino Acids, Ed. G. C. Barrett, Chapman and Hall,London 1985.

Compounds of formula (II) may be prepared from a suitably protectedcompound of formula (V): ##STR7## wherein R¹, R³, R⁴, and Z are asdefined for formula (I) and R³⁰ is an amine protecting group, forexample, tert-butoxycarbonyl (t-BOC), by reaction with a compound offormula (V) using the conditions of process (C), followed bydeprotection in a conventional manner, for instance using hydrogenchloride in methanol.

Compounds of formula (III) may be prepared from a deprotected derivativecorresponding to a compound of formula (V) by reaction with an aldehydeof formula R² --CHO under the conditions of process (A) or an acylhalide of formula R² --COHal under the conditions of process (B).

Compounds of formula (V) may be prepared by reaction of a compound offormula (VI): ##STR8## wherein R³, R⁴, and Z are as defined for formula(I) and R³⁰ is a protecting group as defined above, by reaction withcompound of the formula R¹ --CH₂ L, where L is a leaving group, forexample, a halogen atom such as chlorine, bromine or iodine, or analkyl- or arylsulphonyloxy group such as a mesylate or tosylate group.The reaction is effected in the presence of a suitable base, forexample, an alkali metal hydride such as sodium hydride.

Compounds of formula (VI) are commercially available or may be preparedby known procedures.

Where the above-described process for the preparation of the compoundsaccording to the invention gives rise to mixture of stereoisomers theseisomers may, if desired, be separated, suitably by conventionaltechniques such as preparative chromatography.

The novel compounds which contain one or more chiral centres may beprepared in racemic form, or individual enantiomers may be preparedeither by enantiospecific synthesis or by resolution.

During any of the above synthetic sequences it may be necessary and/ordesirable to protect sensitive or reactive groups on any of themolecules concerned. This may be achieved by means of conventionalprotecting groups, such as those described in Protective Groups inOrganic Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973; and T. W.Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, JohnWiley & Sons, 1991. The protecting groups may be removed at a convenientsubsequent stage using methods known from the art.

The exemplified compounds of the invention were tested by the methodsset out at pages 82 to 85 of International Patent Specification No.93/04040. The compounds were found to be active with IC₅₀ at the NK₁receptor of less than 300 nM.

The compounds of this invention may be formulated as specificallyillustrated at pages 81 to 82 of International Patent Specification No.93/04040.

The following Examples illustrate the preparation of compounds accordingto the invention.

DESCRIPTION 1 N-1-methanesulfonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-(t-butoxycarbonylamino)propionamide

To N-tert-butoxycarbonyl-O-benzyl-d,l-serine (2.9 g, 9.83 mmol), and1-hydroxybenzotriazole (278 mg), was added dry dimethylformamide (30ml), and the mixture cooled to 4° C.1-(3-Dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (2.36 g)was added, and the resulting mixture stirred for 1 hour at roomtemperature. The resulting solution was then cooled to -15° C. and1-methanesulfonylspiro(3H-indole-3,4'-piperidine) hydrochloride (2.93 g)was then added, followed after stirring for 5 minutes, by triethylamine(1.50 ml). The resulting mixture was warmed to room temperature, stirredat room temperature for 1.5 hours, then diluted with ethyl acetate (150ml), washed with water (100 ml), and saturated aqueous sodium hydrogencarbonate (50 ml). The organic layer was dried over sodium sulfate,filtered, and solvents evaporated at reduced pressure. The residue wassubjected to chromatogrmphy on silica gel (eluent 5%methanol/dichloromethane) to afford the title compound as a colourlesssolid. m/e (Cl⁺) 544 (MH⁺). m.p. 53°-56° C.

DESCRIPTION 2 N-1-methanesulfonylspiro(3H-indole-3,4'-piperidin)-1-yl!-2-amino-3-benzyloxypropionamidehydrochloride

To the product of Description 1 (0.48 g, 1 mmol), was added a saturatedsolution of hydrogen chloride in methanol (150 ml). The resultingsolution was allowed to stand at room temperature for 24 hours. Afterevaporation of the volatiles at reduced pressure, the residue wasdissolved in dichloromethane (50 ml), then diluted with diethyl ether(150 ml). Trituration of the mixture afforded the title compound as acolourless solid, recovered by filtration. Found: C, 56.65; H, 6.62; N,8.45. C₂₃ H₂₉ N₃ O₄ S.HCl.0.5(H₂ O) requires: C, 56.48 H, 6.39; N,8.59%. m/e (Cl⁺) 444 (MH⁺).

EXAMPLE 1 N-1-methanesulfonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-(3,4-dichlorobenzamido)propionanmide

To the product of Description 2 (1.15 g, 2.4 mmol), dissolved in drydichloromethane (5 ml), stirred at 4° C., was added triethylamine (0.700ml), followed by 3,4-dichlorobenzoyl chloride (552 mg), and4-dimethylaminopyridine (10 mg). The resulting mixture was warmed toroom temperature and then stirred for a further 3 hours. The reactionmixture was diluted with ethyl acetate (50 ml) and washed with saturatedaqueous sodium hydrogen carbonate (50 ml). The organic layer was driedover sodium sulfate, filtered, and solvents evaporated at reducedpressure. The residue was subjected to chromatography on silica gel(eluent 5% methanol/dichloromethane) to afford the title compound as acolourless foam. Found: C, 58.71; H, 5.06; N, 6.74. C₃₀ H₃₁ N₃ O₅ SClrequires: C, 58.44 H, 5.07; N, 6.85%. m/e (Cl⁺) 616 (MH⁺).

EXAMPLE 2 N-1-methanesulfonylspiro(3H-indole-3,4'-piperidin)-1-yl-3-benzyloxy-2-(3,4-dichlorobenzylamino)propionamidehydrochloride

a) N-1-methanesulfonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-aminopropionamide

The product of Description 2 was stirred vigorously with saturatedaqueous sodium carbonate and ethyl acetate for 30 minutes. The organiclayer was then separated, dried over sodium sulfate, filtered, andsolvents evaporated at reduced pressure to afford the title compound.

b) N1-methanesulfonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-(3,4-dichlorobenzylamino)propionamidehydrochloride

To the product of step (a) (590 mg, 1.33 mmol), dissolved in drydichloromethane (2.5 ml), was added 3,4-dichlorobenzaldehyde (260 mg),and anhydrous magnesium sulfate (1.3 g). The resulting mixture wasstirred for 18 hours, then diluted with dichloromethane (50 ml) filteredand the solvents evaporated at reduced pressure. The residue wasdissolved in methanol (3 ml) and sodium borohydride (55 mg) added withstirring. The resulting mixture was stirred for 1 hour at roomtemperature, and the solvents evaporated at reduced pressure. Theresidue was partitioned between water (15 ml) and ethyl acetate (25 ml).The organic layer was separated, dried over sodium sulfate, filtered,and solvents evaporated at reduced pressure. The residue was subjectedto chromatography on silica gel (eluent 2.5% methanol/dichloromethane)to afford a colourless foam. This was dissolved in ethyl acetate, andtreated with a saturated solution of hydrogen chloride in ether. Thetitle compound was isolated by filtration as a colourless solid. Found:C, 56.64; H, 5.25; N, 6.61. C₃₀ H₃₃ N₃ O₄ SCl₂.HCl requires: C, 56.39 H,5.36; N, 6.58% m/e (Cl⁺) 602 (MH⁺).

EXAMPLE 3 N-1-methanesulfonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-(3-pyridylcarboxamido)propionamide

To nicotinic acid (77 mg), and 1-hydroxybenzotriazole (85 mg), in drydimethylformamide (2.5 ml), was added1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (120 mg),and the resulting mixture stirred for 1 hour at room temperature.Triethylamine (0.087 ml) was then added, followed by the product ofDescription 2 (300 mg). The resulting mixture was stirred at roomtemperature for 16 hours, then diluted with ethyl acetate (50 ml),washed with water (100 ml), and saturated aqueous sodium hydrogencarbonate (25 ml). The organic layer was dried over sodium sulfate,filtered, and solvents evaporated at reduced pressure. The residue wassubjected to chromatography on silica gel (eluent ethyl acetate) toafford the title compound as a colourless solid. m/e (Cl⁺) 549 (MH⁺).m.p. 80°-83° C.

EXAMPLE 4N-1-methanesulfonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-(2-methoxybenzylamino)propionamidehydrochloride

To the product of Description 2 (0.48 g, 1 mmol), in drydimethylformamide (1 ml), was added 2-methoxybenzaldehyde (0.11 g, 1.1mmol), followed by sodium cyanoborohydride (0.09 g, 2 mmol), and themixture stirred at room temperature for 16 hours. The reaction wasdiluted with ethyl acetate (20 ml), and washed with water (5×10 ml),dried over magnesium sulfate, filtered, and the solvent evaporated atreduced pressure. The residue was purified by chromatography on silicagel, (eluent 1% methanol/dichloromethane), to afford the title compound.Found: C, 61.84; H, 6.43; N, 6.68. C₃₁ H₃₇ N₃ O₅ S.HCl.0.25(H₂ O)requires: C, 61.58; H, 6.42; N, 6.95%. m/e (Cl⁺) 564 (MH⁺).

By the method of Example 2, or Example 4, the following compounds wereprepared from the known aldehydes.

EXAMPLE 5 N-1-methanesulfonylspiro(3H-indole-3,4'-piperidin)-1-yl!-2-(benzylamino)-3-benzyloxypronionamide,hydrochloride

Found: C, 61.47; H, 6.31; N, 7.62. C₃₀ H₃₅ N₃ O₄ S.HCl.H₂ O requires: C,61.47; H, 6.31; N, 7.62%.

EXAMPLE 6 N1-methanesulfonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-(2-chlorobenzylamino)propionamidehydrochloride

Found: C, 58.90; H, 5.80; N, 6.69. C₃₀ H₃₄ N₃ O₄ SCl.HCl.0.25(H₂ O)requires: C, 59.16; H, 5.88; N, 6.90%. m/e (Cl⁺) 568 (MH⁺)

EXAMPLE 7 N-1-methanesulfonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-(3-chorobenzylamino)propionamidehydrochloride

Found: C, 58.23; H, 5.78; N, 6.63. C₃₀ H₃₄ N₃ O₄ SCl.HCl.H₂ O requires:C, 57.87; H, 5.99; N,6.74%. m/e (Cl⁺) 568 (MH⁺).

EXAMPLE 8 N-1-methanesulfonylsoiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-(4-chlorobenzylamino)propionamidehydrochloride

Found: C, 58.59; H, 5.93; N, 6.76. C₃₀ H₃₄ N₃ O₄ SCl.HCl.0.5(H₂ O)requires: C, 58.72; H, 5.91; N, 6.85%. m/e (Cl⁺) 568 (MH⁺).

EXAMPLE 9 N-1-methanesulfonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-(3-bromobenzylamino)propionamidehydrochloride

Found: C, 54.08; H, 5.57; N, 6.16. C₃₀ H₃₄ N₃ O₄ SBrHCl.H₂ O requires:C, 54.01; H, 5.59; N, 6.29%. m/e (Cl⁺) 614 (MH⁺).

EXAMPLE 10 N-1-methanesulfonylspiro(3H-indole-3,4'-piperidine)-1-yl!-3-benzyloxy-2-(3-fluorobenzylamino)propionamide,hydrochloride

Found: C, 60.24; H, 5.94; N, 6.76. C₃₀ H₃₄ N₃ O₄ SF.HCl.0.5(H₂ O)requires: C, 60.34; H, 6.08; N, 7.04%. m/e (Cl⁺) 552 (MH⁺).

EXAMPLE 11 N-1-methanesulfonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-(3-cyanobenzylamino)propionamidehydrochloride

Found: C, 60.42; H, 5.78; N, 8.81. C₃₀ H₃₄ N₄ O₄ S.HCl.H₂ O requires: C,60.72; H, 6.08; N, 9.13%. m/e (Cl⁺) 559 (MH⁺).

EXAMPLE 12 N-1-methanesulfonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-(3-nitrobenzylamino)propionamidehydrochloride

Found: C, 56.99; H, 5.64; N, 8.64. C₃₀ H₃₄ N₄ O₆ S.HCl.H₂ O requires: C,56.91; H, 5.84; N, 8.85%. m/e (Cl⁺) 579 (MH⁺).

EXAMPLE 13 N-1-methanesulfonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-(3-methylbenzylamino)propionamidehydrochloride

Found: C, 61.79; H, 6.64; N, 6.83. C₃₄ H₃₇ N₃ O₄ S.HCl.H₂ O requires: C,61.83; H, 6.69; N, 6.97%. m/e (Cl⁺) 548 (MH⁺).

EXAMPLE 14 N-1-methanesulfonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-(3-methoxybenzylamino)propionamide,hydrochloride

Found: C, 60.06; H, 6.32; N, 6.41. C₃₁ H₃₇ N₃ O₅ S.HCl.H₂ O requires: C,60.23; H, 6.52; N, 6.79%. m/e (Cl⁺) 564 (MH⁺).

EXAMPLE 15 N-1-methanesulfonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-(4-methoxybenzylamino)pronionamide,hydrochloride

Found: C, 58.89; H, 6.40; N, 6.94. C₃₁ H₃₇ N₃ O₅ S.HCl.2(H₂ O) requires:C, 58.53; H, 6.65; N, 6.61%. m/e (Cl⁺) 564 (MH⁺).

EXAMPLE 16 N-1-methanesulfonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-(4-(dimethylamino)-benzylamino)propionamidehydrochloride

Found: C, 57.67; H, 6.42; N, 7.96. C₃₂ H₄₀ N₄ O₄ S.2(HCl).(H₂ O )requires: C, 57.56; H, 6.64; N, 8.39%. m/e (Cl⁺) 577 (MH⁺).

EXAMPLE 17 N-1-methanesulfonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-(2,4-dichlorobenzylamino)propionamidehydrochloride

Found: C, 55.20; H, 5.58; N, 6.14. C₃₀ H₃₃ N₃ O₄ SCl₂ HCl.0.5(H₂ O)requires: C, 55.60; H, 5.44; N, 6.48%. m/e (Cl⁺) 602 (MH⁺).

EXAMPLE 18 N-1-methanesulfonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-(3,5-dichlorobenzylamino)propionamidehydrochloride

Found: C, 54.96; H, 5.47; N, 6.45. C₃₀ H₃₃ N₃ O₄ SCl₂.HCl.H₂ O requires:C, 54.84; H, 5.53; N, 6.40%. m/e (Cl⁺) 602 (MH⁺).

EXAMPLE 19 N-1-methanesulfonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-(2,3-dichlorobenzylamino)propionamidehydrochloride

Found: C, 54.48; H, 5.13; N, 6.36. C₃₀ H₃₃ N₃ O₄ SCl₂.HCl.H₂ O requires:C, 54.84; H, 5.53; N, 6.40%. m/e (Cl⁺) 602 (MH⁺).

EXAMPLE 20 N-1-methanesulfonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-(2,6-dichlorobenzylamino)propionamidehydrochloride

m/e (Cl⁺) 602 (MH⁺).

EXAMPLE 21 N-1-methanesulfonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-(3,5-dimethoxybenzylamino)propionamidehydrochloride

Found: C, 59.83; H, 6.40; N, 6.62. C₃₂ H₃₉ N₃ O₆ S.HCl.0.5(H₂ O)requires: C, 60.13; H, 6.47; N, 6.57%. m/e (Cl⁺) 594 (MH⁺).

EXAMPLE 22 N-1-methanesulfonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-(3-chloro-5-methoxybenzylamino)propionamidehydrochloride

Found: C, 57.22; H. 5.88; N, 6.35. C₃₃ H₃₆ N₃ O₅ SCl.HCl.H₂ O requires:C, 56.96; H, 6.16; N, 6.42%. m/e (Cl⁺) 598 (MH⁺).

EXAMPLE 23 N-1-methanesulfonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-(3,4-dimethoxybenzylamino)propionamide,hydrochloride

Found: C, 60.12; H, 6.68; N, 6.52. C₃₂ H₃₉ N₃ O₆ S.HCl.0.5(H₂ O)requires: C, 60.13; H, 6.47; N, 6.57%. m/e (Cl⁺) 594 (MH⁺).

EXAMPLE 24 N-1-methanesulfonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-(3,4-methylenedioxybenzylamino)propionamidehydrochloride

Found: C, 59.98; H, 6.01; N, 6.64. C₃₁ H₃₅ N₃ O₆ S.HCl.0.25(H₂ O)requires: C, 60.18; H, 5.95; N, 6.79%. m/e (Cl⁺) 578 (MH⁺).

EXAMPLE 25 N-1-methanesulfonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-(1-naphthylmethylamino)propionamide,hydrochloride

Found: C, 64.71; H, 6.25; N, 6.58. C₃₄ H₃₇ N₃ O₄ S.HCl.0.5(H₂ O)requires: C, -64.90; H, 6.24; N, 6.67%. m/e (Cl⁺) 584 (MH⁺).

EXAMPLE 26 N-1-methanesulfonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-(2-naphthylmethylamino)propionamidehydrochloride

Found: C, 63.72; H, 5.99; N, 6.51. C₃₄ H₃₇ N₃ O₄ S.HCl.H₂ O requires: C,63.98; H, 6.31; N, 6.58%. m/e (Cl⁺) 584 (MH⁺).

EXAMPLE 27 N-1-methanesulfonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-(2-pyridylmethylamino)propionamidedihydrochloride

Found: C, 56.88; H, 6.22; N, 9.42. C₂₉ H₃₄ N₄ O₄ S.2(HCl).0.5(H₂ O)requires: C, 56.91; H, 6.01; N, 9.15%. m/e (Cl⁺) 535 (NM⁺). mp =98° C.

EXAMPLE 28 N-1-methanesulfonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-(3-pyridylmethylamino)propionamidedihydrochloride

m/e (Cl⁺) 535 (MH⁺). mp=156°-158° C.

EXAMPLE 29 N-1-methanesulfonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-(4-pyridylmethylamino)pronionamidedihydrochloride

m/e (Cl⁺) 535 (MH⁺). mp=135°-137° C.

EXAMPLE 30 N-1-methanesulfonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-(2-furylmethylamino)propionamidedihydrochloride

m/e (Cl⁺) 524 (MH⁺). mp=112° C.

EXAMPLE 31 N-1-methanesulfonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-(5-methylfur-2-yl)methylamino!propionamide hydrochloride

Found: C, 58.66; H, 6.78; N, 7.29. C₂₉ H₃₅ N₃ O₅ S. HCl.H₂ O requires:C, 58.82; H, 6.47; N, 7.09%. m/e (Cl⁺) 537 (MH⁺).

EXAMPLE 32 N-1-methanesulfonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-(3-methylthiophen-2-yl)methylamino!propionamide hydrochloride

Found: C, 57.85; H, 6.30; N, 6.64. C₂₉ H₃₅ N₃ O₄ S2.HCl.1.5(H₂ O)requires: C, 57.79; H, 6.10; N, 6.97%. m/e (Cl⁺) 554 (MH⁺).

EXAMPLE 33 N-1-methanesulfonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-(5-methylthiophen-2-yl)methylamino!propionamide hydrochloride

Found: C, 55.70; H, 6.15; N, 6.40. C₂₉ H₃₅ N₃ O₄ S₂.HCl.2(H₂ O)requires: C, 55.62; H, 6.43; N, 6.71%. m/e (Cl⁺) 554 (MH⁺).

EXAMPLE 34 N-1-methanesulfonylspiro(3H-indole-3,4'-piperidin)-1l-yl!3-benzyloxy-2-(N-(3,4-dichlorobenzyl)-N-(methyl)amino)propionamidehydrochloride

To the product of Example 2 (113 mg, 0. 188 mmol), suspended in drydimethylformamide (2 ml), was added sodium cyanoborohydride (44 mg),paraformaldehyde (100 mg), and the mixture was stirred at roomtemperature for 16 hours. The reaction was diluted with ethyl acetate(20 ml), and washed with water (5×10 ml), dried over magnesium sulfate,filtered, and the solvent evaporated at reduced pressure. The residuewas purified by chromatography on silica gel, (eluent 2.5%methanol/dichloromethane), to afford the title compound. Found: C,56.05; H, 5.77; N, 6.35. C₃₁ H₃₅ N₃ O₄ SCl₂.HCl.0.5(H₂ O) requires: C,56.24; H, 5.63; 6.35%. m/e (Cl⁺) 616 (MH⁺).

By the method of Example 1 the following compounds were prepared fromthe known acid chlorides and the product of Description 2:

EXAMPLE 35 N-1-methanesulfonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-(2-chlorobenzamido)propionamide

Found: C, 62.27; H,, 5.79; N, 6.91. C₃₀ H₃₂ N₃ O₅ SCl requires: C,61.90; H, 5.54; N, 7.22%. m/e (Cl⁺) 582 (MH⁺).

EXAMPLE 36 N-1-methanesulfonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-(3-chlorobenzamido)pronionamide

Found: C, 61.78; H, 5.54; N, 6.96. C₃₀ H₃₂ N₃ O₅ SCl requires: C, 61.90;H, 5.54; N, 7.22%. m/e (Cl⁺) 582 (MH⁺).

EXAMPLE 37 N-1-methanesulfonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-(4-chlorobenzamido)propionamide

Found: C, 61.10; H, 5.49; N, 6.86. C₃₀ H₃₂ N₃ O₅ SCl.0.5(H₂ O )requires:C, 60.95; H, 5.63; N, 7.11%. m/e (Cl⁺) 582 (MH⁺).

EXAMPLE 38 N-1-methanesulfonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-(2,6-dichlorobenzamido)propionamide

Found: C, 56.51; H, 4.80; N, 6.34. C₃₀ H₃₁ N₃ O₅ SCl₂.H₂ O requires: C,56.78; H, 5.24; N, 6.62%. m/e (Cl⁺) 616 (MH⁺).

EXAMPLE 39 N-1-methanesulfonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-(3,5-dichlorobenzamido)pronionamide

Found: C, 58.34; H, 4.73; N, 6.64. C₃₀ H₃₁ N₃ O₅ SCl₂ requires: C,58.44; H, 5.06; N, 6.81%. m/e (Cl⁺) 616 (MH⁺).

EXAMPLE 40 N-1-methanesulfonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-(2,5-dichlorobenzamido)propionamide

Found: C, 56.80; H, 4.94; N, 6.53. C₃₀ H₃₁ N₃ O₅ SCl₂.H₂ O requires: C.56.78 H, 5.24; N, 6.62%. m/e (Cl⁺) 616 (MH⁺).

EXAMPLE 41 N-1-methanesulfonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-(2,4-dichlorobenzamido)propionamide

Found: C, 57.67; H, 4.86; N, 6.30. C₃₀ H₃₂ N₃ O₅ SCl₂.0.6(H₂ O)requires: C, 57.43; H, 5.17; N, 6.70%. m/e (Cl⁺) 616 (MH⁺).

EXAMPLE 42 N-1-methanesulfonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-(2,3-dichlorobenzamido)propionamide

Found: C, 58.22; H, 4.86; N, 6.69. C₃₀ H₃₁ N₃ O₅ SCl₂ requires: C,58.44; H, 5.06; N, 6.81%. m/e (Cl⁺) 616 (MH⁺).

EXAMPLE 43 N-1-methanesulfonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-(3,4-dimethoxybenzamido)propionamide

Found: C, 59.50; H, 6.17; N, 6.35. C₃₂ H₃₇ N₃ O₇ S.2(H₂ O) requires: C,59.70 H, 6.42; N, 6.53%. m/e (Cl⁺) 608 (MH⁺).

EXAMPLE 44 N-1-methanesulfonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-benzamidopropionamide

Found: C, 65.69; H, 5.84 N, 7.56. C₃₀ H₃₃ N₃ O₅ S requires: C, 65.79; H,6.07; N, 7.67%. m/e (Cl⁺) 547 (MH⁺).mp=78°-81° C.

EXAMPLE 45 N-1-methanesulfonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-(3-(2-propyloxy)benzamido)propionamide

Found: C, 64.42; H, 6.20; N, 6.76. C₃₃ H₃₉ N₃ o₆ S requires: C, 64.47;H, 6.56; N, 6.83%. m/e (Cl⁺) 606 (MH⁺).

EXAMPLE 46 N-1-methanesulfonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-(1-naphthyl)carboxamido!propionamide

m/e (Cl⁺) 598 (MH⁺).mp=76°-79° C.

EXAMPLE 47 N-1-methanesulfonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-(2-naphthyl)carboxamido!propionamide

m/e (Cl⁺) 598 (MH⁺).mp=86°-89° C.

EXAMPLE 48 N-1-methanesulfonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-(phenylacetamido)propionamide

Found: C, 65.37; H, 6.03; N, 7.17. C₃₁ H₃₅ N₃ O₅ S.0.5(H₂ O ) requires:C, 65.24; H, 6.34; N, 7.36%. m/e (Cl⁺) 562 (MH⁺).

EXAMPLE 49 N-1-methanesulfonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-((3,4-dichlorophenyl)acetamido)propionamide

Found: C, 58.22; H, 5.19; N, 6.28. C₃₁ H₃₃ N₃ O₅ SCl₂.0.5(H₂ O )requires: C, 58.21; H, 5.35; N, 6.57%. m/e (Cl⁺) 630 (MH⁺).

EXAMPLE 50 N-1-methanesulfonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-(3,5-bis(trifluoromethyl)phenyl)acetamido!propionamide

Found: C, 56.86 H. 4.69: N. 5.92. C₃₃ H₃₃ N₃ O₅ SF₆ requires: C, 56.81;H, 4.77; N, 6.02%. m/e (Cl⁺) 698 (MH⁺).

EXAMPLE 51 N-1-methanesulfonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-(diphenylacetamido)propionamide

Found: C, 69.10; H, 6.29; N, 6.25. C₃₇ H₃₉ N₃ O₅ S.0.3(H₂ O) requires:C, 69.09; H, 6.21; N, 6.53%. m/e (Cl⁺) 638 (MH⁺).

By the method of Example 3 the following compounds were prepared fromthe known acids and the product of Description 2:

EXAMPLE 52 N-1-methanesulfonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-(4-pyridylcarboxamido)propionamide

m/e (Cl⁺) 549 (MH⁺). mp=126°-128° C.

EXAMPLE 53 N-1-methanesulfonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-(2-pyridylcarboxamido)propionamidehydrochloride

m/e (Cl⁺) 549 (MH⁺). mp=95°-98° C.

EXAMPLE 54 N-1-methanesulfonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-(8-quinolinylcarboxamido)propionamidehydrochloride

m/e (Cl⁺) 599 (MH⁺). mp=80°-83° C.

N-tert-butoxycarbonylserine was treated with sodium hydride and theappropriate substituted benzyl chlorides or bromides according to themethod of Sugano. H, and Miyoshi. M, J. Org. Chem, 41, 2352, (1976), toafford the corresponding N-tert-butoxycarbonyl-O-benzyl-serine afterester saponification. The following compounds were prepared from theN-tert-butoxycarbonyl-O-benzyl-serines according to the method ofDescriptions 1 or 2, and Examples 1 or 2:

EXAMPLE 55 N-1-methanesulfonylspiro(3H-indole-3,4'-piperidin)-1-yl!-2-(benzylamino)-3-(2-chlorobenzyloxy)propionamidehydrochloride

Found: C, 57.83; H, 5.85; N, 6.30. C₃₀ H₃₂ N₃ O₄ SCl.HCl.1.25(H₂ O )requires: C, 57.64; H, 5.72; N, 6.72%. m/e (Cl⁺) 568 (MH⁺).

EXAMPLE 56 N-1-methanesulfonylspiro(3H-indole-3,4'-piperidin)-1-yl!-2-(1)benzylamino)-3-(3-chlorobenzyloxy)propionamidehydrochloride

Found: C, 56.73; H, 5.89; N, 6.51. C₃₀ H₃₂ N₃ O₄ SCl.HCl.2(H₂ O )requires: C, 56.42; H, 5.84; N, 6.58%. m/e (Cl⁺) 568 (MH⁺).

EXAMPLE 57 N-1-methanesulfonylspiro(3H-indole-3,4'-piperidin)-1-yl!-2-(benzylamino)-3-(4-chlorobenzyloxy)propionamidehydrochloride

Found: C, 58.32; H, 5.81; N, 6.56. C₃₀ H₃₂ N₃ O₄ SCl.HCl.H₂ O requires:C, 58.06; H, 5.68; N, 6.77%. m/e (Cl⁺) 568 (MH⁺).

EXAMPLE 58 N-1-methanesulfonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-(2-chlorobenzyloxy)-2-(3,4-dichlorobenzylamino)propionamidehydrochloride

Found: C, 52.74; H, 4.90; N, 5.96. C₃₀ H₃₂ N₃ O₄ SCl₃.HCl.0.5(H₂ O )requires: C, 52.79; H, 5.02; N, 6.18%. m/e (Cl⁺) 636 (MH⁺).

EXAMPLE 59 N-1-methanesulfonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-(3-chlorobenzyloxy)-2-(3,4-dichlorobenzylamino)propionamidehydrochloride

Found: C, 52.33; H, 5.01; N, 5.75. C₃₀ H₃₂ N₃ O₄ SCl₃.HCl.H₂ O requires:C, 52.10; H, 5.10; N, 6.07%. m/e (Cl⁺) 636 (MH⁺).

EXAMPLE 60 N-1-methanesulfonylspiro(3H-indole-3,4'-piperidin)-1yl-!-3-(4-chlorobenzyloxy)-2-(3,4-dichlorobenzylamino)propionamidehydrochloride

Found: C, 52.36; H, 4.77; N, 6.07. C₃₀ H₃₂ N₃ O₄ SCl₃.HCl.0.5(H₂ O)requires: C, 52.22; H, 4.89; N, 6.09%. m/e (Cl⁺) 636 (MH⁺).

EXAMPLE 61 N- 1-methanesulfonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-3,5-bis(trifluoromethyl)benzyloxy-2-(3,5-dichlorobenzamido)-propionamide

Found: C, 50.99; H, 3.77; N, 5.60. C₃₂ H₂₉ N₃ O₅ SCl₂ F₆ requires: C,51.07; H 3.88; N, 5.58%. m/e (Cl⁺) 752 (MH⁺).

The following compound was prepared fromN-tert-butoxylcarbonyl-S-benzyl-cysteine according to the method ofDescriptions 1 and 2, and Example 2

EXAMPLE 62 N-1-methanesulfonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-(benzylthio)-2-(3,4-dichlorobenzylamino)pronionamide,hydrochloride

Found: C, 54.63; H, 5.11; N, 6.19. C₃₀ H₃₃ N₃ O₃ S₂.HCl requires: C,55.00; H, 5.23; N, 6.41%. m/e (Cl⁺) 618 (MH⁺). m.p. 215°-217° C.

N-tert-Butoxycarbonylserine was treated with sodium hydride and theappropriate substituted benzyl or naphthylmethyl chlorides or bromidesaccording to the method of Sugano, H. and Miyoshi, M., J. Org. Chem.,41, 2352 (1976) to give, after ester saponification, the correspondingO-substituted N-tert-butoxycarbonylserine. The following compounds wereprepared from the O-substituted N-tert-butoxycarbonylserines accordingto the method of Descriptions 1 or 2, and Examples 1 or 2:

EXAMPLE 63 N-1-Methanesulfonylspiro(3H-indole-3,4'-piperidin)-1-yl!-2-(benzylamino)-3-naphth-2-yl)methoxy!propionamide, hydrochloride

Found: C, 64.64; H, 6.27; N, 6.34. C₃₄ H₃₇ N₃ O₄ S.HCl.0.5H₂ O requires:C, 64.90; H, 6.25; N, 6.68%. m/e (CI⁺) 584 (MH⁺).

EXAMPLE 64 N-1-Methanesulfonylspiro(3H-indole-3,4'-piperidin)-1-yl!-2-(benzylamino)-3-(naphth-1-yl)methoxy!propionamide, hydrochloride

Found: C, 63.64; H, 6.28; N, 6.59. C₃₄ H₃₇ N₃ O₄ S.HCl.H₂ O requires: C,63.99; H, 6.32; N, 6.58%. m/e (CI⁺) 584 (MH⁺).

EXAMPLE 65 N-1-Methanesulfonylspiro(3H-indole-3,4'-piperidin)-1-yl!-2-(benzylamino)-3-(3,4-dichlorobenzyloxy)propionamide,hydrochloride

Found: C, 55.53; H, 5.33; N, 6.85. C₃₀ H₃₃ Cl₂ N₃ O₄ S.HCl.0.5H₂ Orequires: C, 55.60; H, 5.44; N, 6.48%. m/e (CI⁺) 602 (MH⁺).

EXAMPLE 66 N- 1-Methanesulfonylspiro(3H-indole-3,4'-piperidin)-1-yl!-2-(3,4-dichlorobenzylamino)-3-(3,4-dichlorobenzyloxyy)propionamide,hydrochloride

Found: C, 49.64; H, 4.42; N, 5.47. C₃₀ H₃₁ Cl₄ N₃ O₄ S.HCl.H₂ Orequires: C, 49.64; H, 4.72; N, 5.79%. m/e (CI⁺) 670 (MH⁺).

EXAMPLE 67 N-1-Methanesulfonylspiro(3H-indole-3,4'-piperidin)-1-yl!-2-!N-(methyl)benzylamino!-3-(3,4-dichlorobenzyloxy)propionamide,hydrochloride

Methyl iodide (0.1 ml) was added to a mixture of N-1-methanesulfonylspiro(3H-indole-3,4'-piperidin)-1-yl!-2-(benzylamino)-3-(3,4-dichlorobenzyloxy)propionamidehydrochloride (48 mg) and potassium carbonate (100 mg) indichloromethane/DMF (1:1, 4 ml) and the mixture was stirred at roomtemperature for 16 hours. The mixture was diluted with ether, washedwith water (3×), dried (Na₂ SO₄) and the solvent was evaporated underreduced pressure. The residue was purified by column chromatography onsilica gel, eluting with ethyl acetate/hexane (3:1). The residue wasdissolved in ethanolic hydrogen chloride and the solvent was evaporatedunder reduced pressure. The residue was triturated with ether and thesolid was collected and dried in vacuo to afford the title compound as acolourless solid. Found: C, 55.28; H, 5.68; N, 6.11. C₃₁ H₃₅ Cl₂ N₃ O₄S.HCl.H₂ O requires: C, 55.48; H, 5.71; N, 6.26%. m/e (CI⁺) 616 (M⁺).

EXAMPLE 68 N-1-Methanesulfonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-(3,4-dichlorobenzyloxy)-2-(dimethyl)aminopronionamide,hydrochloride

a) N-1-Methanesulfonylspiro(3H-indole-3,4'-piperidin)-1-yl!-2-amino-3-(3,4-dichlorobenzyloxy)propionamide

N-tert-Butoxycarbonylserine was treated with sodium hydride and3,4-dichlorobenzyl bromide according to the method of Sugano, H. andMiyoshi, M., J. Org. Chem., 41, 2352 (1976) to give, after estersaponification, N-tert-butoxycarbonyl-O-(3,4-dichlorobenzyl)serine. Thiswas then coupled according to the method of Description 1 anddeprotected according to the method of Description 2 to give the titlecompound. m/e (CI⁺) 512 (MH⁺).

b) N-1-Methanesulfonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-(3,4-dichlorobenzyloxy)-2-(dimethyl)aminopropionamide,hydrochloride

Aqueous formaldehyde (38%, 1 ml) and sodium cyanoborohydride (35 mg)were added to a solution of the product of step (a) (240 mg) inacetonitrile (20 ml). Acetic acid was added until the reaction pH was 5and the mixture was stirred at room temperature for 4 hours. The solventwas evaporated under reduced pressure and the residue was partitionedbetween ethyl acetate and aqueous sodium hydroxide (1M). The organiclayer was dried (MgSO₄) and the solvent was evaporated under reducedpressure. The residue was purified by column chromatography on silicagel, eluting with dichloromethane/methanol (98:2). The residue wasdissolved in ethanolic hydrogen chloride (5M, 3 ml) and the solvent wasevaporated under reduced pressure. The solid was recrystallized fromisopropyl alcohol/ether to afford the title compound as a colourlesssolid (165 mg, 61%). Found: C, 51.14; H, 5.70; N, 7.06. C₂₅ H₃₁ Cl₂ N₃O₄ S.HCl.0.5H₂ O requires: C, 51.24; H, 5.68; N, 7.17%. m/e (CI⁺) 540(MN⁺).

EXAMPLE 69 N-1-Methanesulfonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-(3,4-dichlorobenzylthio)-2-(benzylamino)propionamide,hydrochloride

3,4-Dichlorobenzylmercaptan (0.3 ml, 1.6 mmol) was added dropwise to astirred, cooled (0° C.) suspension of sodium hydride (64 mg, 1.6 mmol)in DMF (5 ml) and the mixture was stirred at 0° C. for 1 hour.N-Benzyl-N-(benzyloxycarbonyl)serine-β-lactone prepared according toVederas, J. C., et. al., J. Am. Chem. Soc., 109, 4649 (1987), 0.40 g,1.2 mmol! in DMF (5 ml) was added and the mixture was warmed to 25° C.and stirred for 2 hours J. Am. Chem. Soc., 107, 7105 (1985)!. Ethylacetate (50 ml) and water (20 ml) were added and the organic layer waswashed with water (3×20 ml), dried (MgSO₄) and the solvent wasevaporated under reduced pressure. The residue was dissolved indichloromethane (10 ml) and1-methanesulfonylspiro(3H-indole-3,4'-piperidine) hydrochloride (0.282g, 1.06 mmol), triethylamine (0.31 ml, 2.2 mmol) andbis(2-oxo-3-oxazolidinyl)phosphinic chloride (0.27 g, 1.06 mmol) wereadded The mixture was stirred at room temperature for 2 hours, thenethyl acetate (50 ml) and water (20 ml) were added. The organic layerwas separated, dried (MgSO₄) and the solvent was evaporated underreduced pressure. The residue was purified by column chromatography onsilica eluting with ethyl acetate/hexane (30:70) to give N-1-methanesulfonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-(3,4-dichlorobenzylthio)-2-N-(benzyl)-benzyloxycarbonylamino!propionamide as a colourless oil (0.80g). A sample (0.10 g) was dissolved in dichloromethane (3 ml), cooled to-10° C. and boron tribromide (1.0M in CH₂ Cl₂, 0.7 ml) was added. Themixture was warmed to 25° C. for 20 minutes, aqueous sodium hydroxide(4M, 5 ml) was added and the mixture was extracted with ethyl acetate(20 ml). The organic layer was dried (MgSO₄) and the solvent wasevaporated under reduced pressure. The residue was treated with etherealhydrogen chloride and the solid was collected and dried in vacuo to givethe title compound as a colorless solid. NMR δ_(H) (360 MHz, DMSO-d₆)7.21-7.48 (10H, m), 7.03 (1H, m), 6.97 (1H, m), 4.05-4.21 (4H, m),3.84-3.96 (2H, 3.64-3.73 (2H, m), 3.22 (1H, m), 2.99 (3H, s), 2.64-2.97(4H, m), 1.67 (2H, m), 1.53 (2H, m). m/e (CI⁺) 618 (MH⁺).

EXAMPLE 70 N-1-Methanesulfonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-(3,4-dichlorobenzylsulfonyl)-2-(benzylamino)propionamide,hydrochloride

m-Chloroperoxybenzoic acid (2.6 g, 8.8 mmol) was added to N-1-methanesulfonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-(3,4-dichlorobenzylthio)-2-N-(benzyl)benzyloxycarbonylamino!propionamide (0.228 g, 0.3 mmol) indichloromethane (2 ml) and the mixture was stirred at room temperaturefor 16 hours. The mixture was diluted with dichloromethane (30 ml) andwashed with aqueous sodium bisulfite (15 ml), aqueous sodium carbonate(15 ml) and brine (15 ml). The organic layer was dried (MgSO₄) and thesolvent was evaporated under reduced pressure. The residue was dissolvedin dichloromethane (1 ml), cooled to -10° C. and boron tribromide (1.0Min CH₂ Cl₂, 0.7 ml) was added. The mixture was warmed to 25° C. for 20minutes, aqueous sodium hydroxide (4M, 5 ml) was added and the mixturewas extracted with ethyl acetate (20 ml). The organic layer was dried(MgSO₄) and the solvent was evaporated under reduced pressure. Theresidue was treated with ethereal hydrogen chloride and the solid wascollected and dried in vacuo to give the title compound as a colorlesssolid. NMR δ_(H) (360 MHz, DMSO-d₆) 7.73 (2H, m), 7.46 (7H, m),7.24-7.34 (2H, m), 7.09 (1H, m), 4.86 (1H, m), 4.78 (2H, s), 4.41 (1H,m), 4.04 (3H, m), 3.94 (2H, s), 3.81 (1H, m), 3.70 (1H, m), 3.24 (1H,m), 3.06 (3H, s), 2.85 (1H, m), 1.75 (4H, m). m/e (CI⁺) 650 (MH⁺).

EXAMPLE 71 N-1-Methanesulfonylspiro(3H-indole-3,4'-piperidin)-1-yl!-2,3-bis(benzylamino)propionamide,hydrochloride

N-bis(trimethylsilyl)amine (0.11 ml, 0.543 mmol) was added to a solutionof N-benzyl-N-benzyloxycarbonyl)serine-β-lactone prepared according toVederas, J. C., et. al., J. Am. Chem. Soc., 109, 4649 (1987), 0.13 g,0.418 mmol! in acetonitrile (2 ml) and the mixture was stirred at roomtemperature for 16 hours Vederas, J. C. et. al. Tetrahedron Lett., 35,7605 (1994)!. The mixture was cooled to 0° C. and aqueous hydrochloricacid (1M, 2 ml) was added. The solvent was evaporated under reducedpressure and the residue was filtered. The filtrate was treated withaqueous sodium hydroxide (2M) until the pH was greater than 10 anddi-tert-butyldicarbonate (200 mg) was added. The mixture was stirred atroom temperature for 12 hours, then ethyl acetate (50 ml) and water (20ml) were added. The organic layer was separated, dried (MgSO₄) and thesolvent was evaporated under reduced pressure. The residue was dissolvedin dichloromethane (10 ml) and1-methanesulfonylspiro(3H-indole-3,4'-piperidine) hydrochloride (0.282g, 1.06 mmol), triethylamine (0.31 ml, 2.2 mmol) andbis(2-oxo-3-oxazolidinyl)phosphinic chloride (0.27 g, 1.06 mmol) wereadded. The mixture was stirred at room temperature for 2 hours, thenethyl acetate (50 ml) and water (20 ml) were added. The organic layerwas separated and dried (MgSO₄) and the solvent was evaporated underreduced pressure. The residue was purified by column chromatography onsilica eluting with ethyl acetate/hexane (30:70). The residue wasdissolved in trifluoroacetic acid (2 ml) and the mixture was stirred atroom temperature for 5 minutes. The solvent was evaporated under reducedpressure and the residue was dissolved in ethanol. Palladium on carbon(0.4 g) was added and the mixture was shaken under hydrogen (50 psi) for16 hours. The mixture was filtered and the solvent was evaporated underreduced pressure. The residue was purified by column chromatography onsilica eluting with CH₂ Cl₂ /MeOH (98:2) and the residue was treatedwith ethereal hydrogen chloride. The solid was collected and dried invacuo to give the title compound as a colourless solid, m.p. 158°-160°C. m/e (CI⁺) 533 (MH⁺).

EXAMPLE 72 N-1-Methanesulfonylspiro(3H-indole-3,4'-piperidin)-1-yl!-2-(benzylamino)-3-(3,4-dichlorobenzylamino)propionamide,dihydrochloride

a) Methyl 2-(tert-butoxycarbonylamino)-3-(3,4-dichlorobenzylamino)propionate

3,4-Dichlorobenzylamine (880 mg) was added to a stirred solution ofmethyl 2-(tert-butoxycarbonylamino)acrylate (390 mg) in methanol (30ml). The reaction mixture was warmed to reflux for 24 hours, cooled toroom temperature and the solvent was evaporated under reduced pressure.The residue was purified by MPLC (70% ethyl acetate/n-hexane) to givethe title compound as a clear oil (300 mg ). NMR δ_(H) (360 MHz, CDCl₃)1.45 (9H, s,) 2.95 (2H, d, J=3.5 Hz), 3.70 (1H, d, J=14.0 Hz), 3.75 (3H,s) 3.78 (1H, d, J=14.0 Hz), 4.41 (1H, br s) 5.34 (1H, br s), 7.12 (1H,dd, J=7.0 and 1.0 Hz), 7.37 (1H, d, J=7.0 Hz), 7.41 (1H, d, J=1.0 Hz).

b) Methyl 2-(tert-butoxycarbonylamino)-3- N-(3,4-dichlorobenzyl)benzyloxycarbonylamino!propionate

Benzylchloroformate (0.37 ml) was added in a single portion to a stirredsuspension of the product of step (a) (1.0 g) in tetrahydrofuran/8%aqueous NaHCO₃ (50 ml). After 2 hours the reaction was diluted withwater (50 ml) and extracted with ethyl acetate (2×50 ml). The combinedorganic fractions were dried (MgSO₄) and the solvent was evaporatedunder reduced pressure to give the title compound as a clear oil (1.09g). NMR δ_(H) (360 MHz, CDCl₃) 1.43 (9H, s), 3.55-3.60 (2H, m), 3.70(3H, s), 4.48 (2H, m), 5.21 (2H, m), 5.41 (1H, br s) 5.45 (1H, br s),6.90-7.42 (8H, m).

c) 2-(tert-Butoxycarbonylamino)-3- N-(3,4-dichlorobenzyl)benzyloxycarbonylamino!propionic acid

Lithium hydroxide (62.4 mg) was added to a solution of the product ofstep (b) (1.0 g) in tetrahydrofuran/water (30 ml). The resultingsolution was stirred at room temperature for 4 hours, diluted with 1NHCl (50 ml) and extracted with ethyl acetate (3×50 ml). The combinedorganic fractions were dried (MgSO₄) and the solvent was evaporatedunder reduced pressure to give the title compound as a colourless foam(990 mg). NMR δ_(H) (360 MHz, CDCl₃) 1.44 (9H, s), 3,49 (2H, m), 4.51(3H, m), 5.17 (2H, m), 5.79 (1H, br s), 7.20-7.42 (8H, m). m/e (CI⁺) 497(MH⁺).

d) N- 1-Methanesulfonylspiro(3H-indole-3,4'-piperidin)-1-yl!-2-amino -3-N-(3,4-dichlorobenzyl)benzyloxycarbonylamino!propionamide

Bis(2-oxo-3-oxazolidinyl)phosphinic chloride (762 mg) was added tostirred solution of the product of step (c) (990 mg),1-methanesulfonylspiro(3H indole-3,4'-piperidine) (580 mg) andtriethylamine (0.85 ml) in dichloromethane (50 ml). The resultingsolution was stirred at room temperature for 18 hours, and the solventwas evaporated under reduced pressure. The residue was partitionedbetween ethyl acetate and water, the organic layer was separated, dried(MgSO₄) and the solvent was evaporated under reduced pressure. Therecovered material was taken up in dichloromethane (20 ml) andtrifluoroacetic acid (2.0 ml) was added. After 2 hours the solvent wasevaporated under reduced pressure and the residue was partitionedbetween aqueous sodium carbonate (saturated, 20 ml) and ethyl acetate(20 ml). The organic layer was separated, dried (MgSO₄) and the solventwas evaporated under reduced pressure to give the title compound as acolourless foam (1.17 g). m/e (CI⁺) 645 (MH⁺).

e) N-1-Methanesulfonylspiro(3H-indole-3,4'-piperidin)-1-yl!-2-(benzylamino)-3-N-(3,4-dichlorobenzyl)benzyloxycarbonyl-amino!pronionamide

Benzaldehyde (171 mg) was added to a solution of the product of step (d)(1.17 g) in dichloromethane (50 ml) stirring over MgSO₄. After 18 hoursthe solution was filtered and the solvent was evaporated under reducedpressure. The residue was dissolved in methanol (20 ml) and treated withsodium borohydride (68 mg). After 2 hours the solvent was evaporatedunder reduced pressure and the residue was partitioned between ethylacetate and water. The organic layer was dried (MgSO₄) and the solventwas evaporated under reduced pressure. The residue was purified by MPLCCH₂ Cl₂ /MeOH/NH₃ (Aq.), 96:3:1! to give the title compound as acolourless solid (410 mg). m/e (CI⁺) 734 (MH⁺).

f) N-1-Methanesulfonylspiro(3H-indole-3,4'-piperidin)-1-yl!-2-(benzylamino)-3-(3,4-dichlorobenzylamino)propionamide,dihydrochloride

Boron tribromide (51.4 mg) was added to a stirred solution of theproduct of step (e) (190 mg) in dichloromethane at -5° C. After 20minutes aqueous sodium hydroxide (4M) was added and the mixture wasextracted with ethyl acetate (4×20 ml). The combined organic fractionswere dried (MgSO₄) and the solvent was evaporated under reducedpressure. The residue was purified by MPLC CH₂ Cl₂ /MeOH/NH₃ (Aq.),96:3:1!. The residue was dissolved in ethanolic hydrogen chloride (5M)and the solvent was evaporated under reduced pressure. The residue wastriturated with isopropanol and the solid was collected and dried invacuo to give the title compound as a colourless solid (37 mg). NMRδ_(H) (250 MHz, DMSO-d₆) 1.63-1.80 (4H, m), 2.09 (3H, m), 2.46-2.70 (3H,m), 2.84 (3H, s), 3.46-3.83 (5H, s) 4.56 (1H, m), 6.87-7.34 (12H, m).m/e (CI⁺) 601 (MH⁺).

EXAMPLE 73 N-1-Methanesulfonylspiro(3H-indole-3,4'-piperidin)-1-yl!-2-(benzylamino)-3-(N-methyl-3,4-dichlorobenzylamino)propionamide,dihydrochloride

a) Methyl2-(tert-butoxycarbonylamino)-3-(N-methyl-3,4-dichlorobenzylamino)propionate

Sodium cyanoborohydride (121 mg) was added to a solution of formaldehyde(570 mg), methyl2-(tert-butoxycarbonylamino)-3-(3,4-dichlorobenzylamino)propionate (720mg) and acetic acid (0.1 ml) in acetonitrile and the mixture was stirredat room temperature for 30 minutes. Aqueous sodium hydrogen carbonate(10 ml) was added and the mixture was extracted with ethyl acetate (3×20ml). The combined organic fractions were dried (MgSO₄) and the solventwas evaporated under reduced pressure to give the title compound as acolourless oil (722 mg). NMR δ_(H) (360 MHz, CDCl₃) 1.45 (9H, s), 2.21(3H, s), 2.73 (2H, d, J=7.0 Hz), 3.46 (2H, m), 3.75 (3H, s) 4.37 (1H,m), 5.19 (1H, br s), 7.10 (1H, dd, J=11.0 and 1.0 Hz), 7.36 (2H, m).

b)2-(tert-Butoxycarbonylamino)-3-(N-methyl-3,4-dichlorobenzylamino)propionicacid

Lithium hydroxide (55 mg) was added to a solution of the product of step(a) (722 mg) in tetrahydrofuran/water (30 ml). The mixture was stirredat room temperature for 4 hours, diluted with hydrochloric acid (1M, 50ml) and extracted with ethyl acetate (3×50 ml). The combined organicfractions were dried (MgSO₄) and the solvent was evaporated underreduced pressure to give the title compound as a colourless foam (301mg). NMR δ_(H) (250 MHz, CDCl₃) 1.43 (9H, s), 2.59 (3H, s), 2.90 (1H,m), 3.22 (1H, m), 3.77 (1H, m) 4.10 (1H, m), 4.26 (1H, m),5.67 (1H, brs) 7.24 (1H, dd, J=11.0 and 1.0 Hz), 7.68 (2H,m). m/e (CI⁺) 377 (MH⁺).

c) N- 1-Methanesulfonylspiro(3H-indole-3,4'-piperidin)-1-yl!-2-amino -3-N-methyl-3,4-dichlorobenzylamino!propionamide

Bis(2-oxo-3-oxazolidinyl)phosphinic chloride (305 mg) was added tostirred solution of the product of step (b) (301 mg),N-1-methanesulfonylspiro(3H-indole)-3,4'-piperidine (230 mg) andtriethylamine (0.36 ml) in dichloromethane (50 ml). The mixture wasstirred at room temperature for 18 hours and the solvent was evaporatedunder reduced pressure. The residue was partitioned between ethylacetate and water and the organic layer was dried (MgSO₄) and thesolvent was evaporated under reduced pressure. The residue was dissolvedin dichloromethane (20 ml) and trifluoroacetic acid (2.0 ml) was added.After 2 hours the solvent was evaporated under reduced pressure and theresidue was partitioned between aqueous sodium carbonate (saturated, 20ml) and ethyl acetate (20 ml). The organic layer was dried (MgSO₄) andthe solvent was evaporated under reduced pressure to give the titlecompound as a colourless foam. (380 mg). m/e (CI⁺) 525 (MH⁺).

d) N-1-Methanesulfonylspiro(3H-indole-3,4'-piperidin)-1-yl!-2-(benzylamino)-3-(N-methyl-3,4-dichlorobenzylamino)propionamidedihydrochloride

Benzaldehyde (80 mg) was added to a solution of the product of step (c)(380 mg) in dichloromethane (50 ml) stirring over MgSO₄. After 18 hoursthe solution was filtered and the solvent was evaporated under reducedpressure. The residue was dissolved in methanol (20 ml) and treated withsodium borohydride (29 mg). After 2 hours the solvent was evaporatedunder reduced pressure and the residue was partitioned between ethylacetate and water. The organic layer was dried (MgSO₄) and the solventwas evaporated under reduced pressure. The residue was purified by MPLCCH₂ Cl₂ /MeOH/NH₃ (Aq.), 96:3:1!. The residue was dissolved in ethanolichydrogen chloride (5M) and the solvent was evaporated under reducedpressure. The residue was triturated with isopropanol and the solid wascollected and dried in vacuo to give the title compound as a colourlesssolid (220 mg). NMR δ_(H) (360 MHz, DMSO-d6) 1.60-2.09 (7H, m),2.50-2.72 (3H, m), 2.91 (3H, s), 2.93 (3H, s) 3.46-3.38 (5H, 5) 4.47(1H, m), 6.87-7.34 (12H, m). m/e (CI⁺) 615 (MH⁺).

EXAMPLE 74 N-1-Methanesulfonylspiro(3H-indole-3,4'-piperidin)-1-yl!-2-(benzylamino)-5-phenylpentanamide,hydrochloride

a) 2- N-(Benzyl)benzyloxycarbonyl!amino-5-phenylpentanoic acid

N-Benzyl-N-(benzyloxycarbonyl)serine-β-lactone prepared according toVederas, J. C., et. al., J. Am. Chem. Soc., 109, 4649 (1987), 933 mg, 3mmol! in THF (10 ml) was added dropwise to a stirred, cooled (-78° C.)solution of phenylethyl magnesium bromide dimethyl sulfide complexprepared from phenylethyl bromide (1.85 g, 10 mmol), magnesium (0.24 g,10 mmol), copper (I) bromide dimethylsulfide complex (50 mg) anddimethylsulfide (0.5 ml) in THF (20 ml) (Vederas, J. C., et. al., J. Am.Chem. Soc., 109, 4649 (1987)!. The mixture was stirred at -78° C. for 30minutes then at -23° C. for 2 hours. Aqueous hydrochloric acid (0.1M, 20ml) was added and the mixture was extracted with ethyl acetate (3×25ml). The combined organic fractions were dried (MgSO₄) and the solventwas evaporated under reduced pressure. The residue was purified bycolumn chromatography on silica gel, eluting with ethyl acetate/aceticacid (99.9:0.1) to give the title compound (253 mg). NMR δ_(H) (250 MHz,CDCl₃) 9.6-9.2 (1H, br s), 7.78-7.35 (15H, m), 5.53 (2H, s), 5.31-4.61(3H, m), 2.78-2.62 (2H, m), and 2.47-1.63 (4H, m).

b) N- 1-Methanesulfonylspiro(3H-indole-3,4'-piperidin)-1-yl!-2-N-(benzylbenzyloxycarbonyl!amino-5-phenylpentanamide

The product of step (a) (250 mg, 0.6 mmol) was dissolved indichloromethane (5 ml) and1-methanesulfonylspiro(3H-indole-3,4'-piperidine) hydrochloride (302 mg,1 mmol), bis(2-oxo-3-oxazolidinyl)phosphinic chloride (254 mg, 2 mmol)and triethylamine (202 mg, 2 mmol) were added. The mixture was stirredat room temperature for 16 hours and the solvent was evaporated underreduced pressure. The residue was dissolved in ethyl acetate, washedwith aqueous potassium carbonate (saturated), dried (MgSO₄) and thesolvent was evaporated under reduced pressure. The residue was purifiedby column chromatography on silica gel, eluting with ethylacetate/hexane to give the title compound (160 mg). m/e (CI⁺) 666 (MH⁺).

c) N-1-Methanesulfonylspiro(3H-indole-3,4'-piperidin)-1-yl!-2-(benzylamino)-5phenylpentanamide,hydrochloride

Boron tribromide (1M solution in dichloromethane, 1 ml) was added to astirred cooled (0° C.) solution of the product of step (b) (150 mg, 0.23mmol) in dichloromethane (1 ml) and the mixture was stirred at 0° C. for30 minutes. Aqueous sodium hydroxide (2M) was added and the organiclayer was washed with water, dried (MgSO₄) and the solvent wasevaporated under reduced pressure. The residue was purified by columnchromatography on silica gel, eluting with dichloromethane/methanol andthe residue was treated with methanolic hydrogen chloride. The solventwas evaporated under reduced pressure and the residue was freeze driedto give the title compound as an amorphous solid (165 mg). Found: C,65.78; H, 6.94; N, 7.65. C₃₁ H₃₇ N₃ O₃ S.HCl requires: C, 65.53; H,6.75; N, 7.40%. m/e (CI⁺) 532 (MH⁺).

EXAMPLE 75 N-1-Methanesulfonylspiro(3H-indole-3,4'-piperidin)-1-yl!-2-(benzylamino)-5-(3,4-dichlorophenyl)pentanamide,hydrochloride

a) Ethyl 5-(3,4-dichlorophenyl-2-oxopentanoate

3-(3,4-Dichlorophenyl)propylmagnesium bromide prepared from3-(3,4-dichlorophenyl)propyl bromide (2.7 g, 10 mmol) and magnesium(0.24 g, 10 mmol) in ether (Ger. Offen. DE1965711)! was added dropwiseto a stirred, cooled (-10° C.) solution of diethyl oxalate (1.75 g, 4.2mmol) in ether (60 ml). THF (15 ml) was added and the mixture wasstirred at room temperature for 0.5 hours. Hydrochloric acid (2M) wasadded and the organic layer was diluted with hexane, washed with brineand aqueous sodium hydrogen carbonate (saturated), dried (MgSO₄) and thesolvent was evaporated under reduced pressure. The residue was purifiedby column chromatography on silica gel, eluting with ethylacetate/hexane (25:75) to give the title compound as an oil (0.7 g). NMRδ_(H) (360 MHz, CDCl₃) 7.35 (1H, d, J=6.4 Hz), 7.28 (1H, d, J=2 Hz),7.01 (1H, dd, J=6.4, 2 Hz), 4.39-4.25 (2H, m), 2.84 (2H, t, J=7.2 Hz),2.62 (2H, t, J=7.2 Hz), 2.09-1.91 (2H, pent, J=8 Hz), and 1.33 (3H, t,J=7 Hz).

b) Ethyl 2-(Benzylamino)-5-(3,4-dichlorophenyl)pentanoate

Acetic acid (0.42 g, 7 mmol) was added to a mixture of the product ofstep (a) (1.0 g, 3.5 mmol), benzylamine (0.75 g, 7 mmol) and sodiumcyanoborohydride (440 mg, 7 mmol) in ethanol (10 ml) and the mixture wasstirred at room temperature for 72 hours. The solvent was evaporatedunder reduced pressure and the residue was partitioned between ethylacetate and aqueous potassium carbonate (saturated). The organic layerwas dried (MgSO₄) and the solvent was evaporated under reduced pressure.The residue was purified by column chromatography on silica gel, elutingwith ethyl acetate/hexane (5:95) to give the title compound (400 mg).NMR δ_(H) (360 MHz, CDCl₃) 7.32-7.23 (7H, m), 6.96 (1H, dd, J=8.4, 2.2Hz), 4.18 (2H, q, J=7 Hz), 3.81 (1H, d, J=12.9 Hz), 3.61 (1H, d, J=12.9Hz), 3.23 (1H, t, J=7.2 Hz), 2.54 (2H, m), 1.69-1.60 (4H, m), and 1.28(3H, t, J=7 Hz).

c) Ethyl 2-N-(benzyl)-tert-butyloxycarbonylamino!-5-(3,4-dichlorophenyl)pentanoate

Di-tert-butyldicarbonate (400 mg) was added to the product of step (b)(400 mg) in dichloromethane (10 ml) and the mixture was stirred at roomtemperature for 72 hours. The solvent was evaporated under reducedpressure and the residue was purified by column chromatography on silicagel, eluting with hexane/ethyl acetate (100:0 increasing to 95:5) togive the title compound (350 mg). NMR δ_(H) (360 MHz, CDCl) 7.29-7.11(6H, m), 7.12-7.11 (1H, m), 6.87-6.85 (1H, m), 4.11-3.88 (5H, m),2.44-1.29 (6H, m), 1.42 (9H, s), and 1.20 (3H, t, J=7 Hz).

d) N- 1-Methanesulfonylspiro(3H-indole-3,4'-piperidin)-1-yl!-2-(benzylamino)-5-(3,4-dichlorophenyl)pentanamide,hydrochloride

A solution of lithium hydroxide (100 mg) in water (10 ml) was added to asolution of the product of step (c) (350 mg) in THF (10 ml) and themixture was stirred at room temperature for 16 hours. The mixture wasacidified with aqueous citric acid (10%) and extracted with ethylacetate (3×25 ml). The combined organic fractions were dried (MgSO₄) andthe solvent was evaporated under reduced pressure. The residue wasdissolved in dichloromethane (5 ml) and1-methanesulfonylspiro(3H-indole-3,4'-piperidine) hydrochloride (215 mg,0.71 mmol), bis(2-oxo-3-oxazolidinyl)phosphinic chloride (199 mg, 0.78mmol) and triethylamine (202 mg, 2 mmol) were added. The mixture wasstirred at room temperature for 16 hours and the solvent was evaporatedunder reduced pressure. The residue was dissolved in ethyl acetate,washed with aqueous potassium carbonate (saturated), dried (MgSO₄) andthe solvent was evaporated under reduced pressure. The residue waspurified by column chromatography on silica gel, eluting with ethylacetate/hexane and the residue was dissolved in ethanolic hydrogenchloride (5M). The solvent was evaporated under reduced pressure and theresidue was freeze dried to give the title compound as an amorphoussolid (235 mg). Found: C, 58.66; H, 5.70; N, 6.60. C₃₁ H₃₅ Cl₂ N₃ O₃S.HCl requires: C, 58.45; H, 5.70; N, 6.60%. m/e (CI⁺) 600 (MH⁺).

EXAMPLE 76 N-1-Methanesulfonylspiro(3H-indole-3,4'-piperidin)-1-yl!-2-(benzylamino)-5-(3,4-dichlorophenyl)butanamide,hydrochloride

a) Ethyl 4-(3,4-Dichlorophenyl)-2-oxobutanoate

2-(3,4-Dichlorophenyl)ethyl bromide (5 g, 19.7 mmol) was added slowly toa suspension of magnesium turnings (0.48 g, 19.7 mmol) in ether (30 ml).After spontaneous reflux had finished the mixture was stirred underreflux for 15 minutes and allowed to cool to room temperature. Themixture was added dropwise via cannula to a stirred, cooled (-25° C.)solution of diethyl oxalate (3 g, 20.7 mmol) in THF (15 ml). The mixturewas stirred at -10° C. for 30 minutes and allowed to warm to roomtemperature. Hydrochloric acid (2M, 15 ml) was added and the mixture wasextracted with ether (2×20 ml). The combined organic fractions werewashed with water, dried (Na₂ SO₄) and the solvent was evaporated underreduced pressure. The residue was purified by column chromatography onsilica gel, eluting with ethyl acetate/hexane (10:90) to give the titlecompound (0.7 g).

b) Ethyl 2-(benzylamino)-4-(3,4-dichlorophenyl)butanoate

A mixture of acetic acid (0.29 ml, 5 mmol), the product of step (a) (700mg, 2.5 mmol), benzylamine (0.56 ml, 5 mmol) and sodium cyanoborohydride(320 mg, 5 mmol) in ethanol (10 ml) was stirred at room temperature for16 hours. The solvent was evaporated under reduced pressure and theresidue was partitioned between ethyl acetate and aqueous sodiumcarbonate (saturated). The organic layer was dried (Na₂ SO₄) and thesolvent was evaporated under reduced pressure. The residue was purifiedby column chromatography on silica gel, eluting with ethylacetate/hexane (10:90) to give the title compound as an oil (310 mg).m/e (CI⁺) 366 (MH⁺).

c) Ethyl 2-N-(benzyl)-tert-butyloxycarbonylamino!-4-(3,4-dichlorophenyl)butanoate

Di-tert-butyldicarbonate (900 mg, 4.1 mmol) was added to the product ofstep (b) (300 mg, 0.82 mmol) in dichloromethane (10 ml) and the mixturewas stirred at room temperature for 5 days. The solvent was evaporatedunder reduced pressure and the residue was purified by columnchromatography on silica gel, eluting with hexane/ethyl acetate (90:10)to give the title compound as an oil (281 mg). m/e (CI⁺) 466 (MH⁺).

d) 2-N-(Benzyl)-tert-butyloxycarbonylamino!-4-(3,4-dichlorophenyl)butanoicacid

Lithium hydroxide (80 mg 1.8 mmol) and water (2 ml) were added to asolution of the product of step (c) (280 mg, 0.6 mmol) in THF (5 ml) andthe mixture was stirred at room temperature for 16 hours. Acetic acid(0.5 ml) was added and the mixture was partitioned between ethyl acetateand water. The organic layer was dried (Na₂ SO₄) and the solvent wasevaporated under reduced pressure to give the title compound as acolourless foam (234 mg) m/e (CI⁺) 438 (MH⁺).

e) N-1-Methanesulfonylspiro(3H-indole-3,4'-piperidin)-1-yl!-2-(benzylamino)-4-(3,4-dichlorophenyl)butanamide,hydrochloride

A mixture of the product of step (e) (230 mg, 0.53 mmol),1-methanesulfonylspiro(3H-indole-3,4'-piperidine) hydrochloride (159 mg,0.53 mmol), bis(2-oxo-3-oxazolidinyl)phosphinic chloride (160 mg, 0.64mmol) and triethylamine (0.18 ml, 1.33 mmol) in dichloromethane (10 ml)was stirred at room temperature for 16 hours. Dichloromethane (10 ml)was added and the mixture was washed with aqueous sodium carbonate(saturated) and aqueous citric acid (10%), dried (Na₂ SO₄) and thesolvent was evaporated under reduced pressure. The residue was purifiedby column chromatography on silica gel, eluting with ethylacetate/hexane (70:30). The residue was dissolved in methanol (2 ml) andmethanolic hydrogen chloride (5 ml) was added. The mixture was stirredat room temperature for 16 hours and the solvent was evaporated underreduced pressure. The residue was dissolved in methanol (2 ml) and etherwas added. The solid was collected and dried in vacuo to give the titlecompound as a colourlesss solid (235 mg). Found: C, 57.36; H, 5.53; N,6.71. C₃₀ H₃₃ Cl₂ N₃ O₃ S.HCl.0.25H₂ O requires: C, 57.42; H, 5.54; N,6.70%. m/e (CI⁺) 586 (NM⁺).

We claim:
 1. A compound of formula (I): ##STR9## wherein n is zero, 1, 2or 3;R represents C₁₋₆ alkyl, C₁₋₆ alkoxy, hydroxy, halogen, cyano,trifluoromethyl, SO₂ C₁₋₆ alkyl, NR^(a) R^(b), NR^(a) COR^(b), orCONR^(a) R^(b), where R^(a) and R^(b) each independently representhydrogen, C₁₋₆ alkyl, phenyl or trifluoromethyl; R¹ representsunsubstituted phenyl or phenyl substituted by 1, 2 or 3 groups selectedfrom C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₃₋₇cycloalkylC¹⁻⁴ alkyl, --O(CH₂)_(p) O-- where p is 1 or 2, halogen,cyano, nitro, trifluoromethyl, trimethylsilyl, OR^(a), SR^(a), SOR^(a),SO₂ R^(a), NR^(a) R^(b), NR^(a) COR^(b), NR^(a) CO₂ R^(b), COR^(a), CO₂R^(a) or CONR^(a) R^(b), where R^(a) and R^(b) are as previouslydefined; naphthyl; benzhydryl; or benzyl, where the naphthyl group oreach phenyl moiety of benzyl and benzhydryl may be substituted by C₁₋₆alkyl, C₁₋₆ alkoxy, halogen or trifluoromethyl; R² represents hydrogen;unsubstituted phenyl or phenyl substituted by 1, 2 or 3 groups selectedfrom C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₃₋₇cycloalkylC₁₋₄ alkyl, --O(CH₂)_(p) O-- where p is 1 or 2, halogen,cyano, nitro, trifluoromethyl, trimethylsilyl, OR^(a), SR^(a), SOR^(a),SO₂ R^(a), NR^(a) R^(b), NR^(a) COR^(b), NR^(a) CO₂ R^(b), COR^(a), CO₂R^(a) or CONR^(a) R^(b), where R^(a) and R^(b) are as previouslydefined; heteroaryl selected from indazolyl, thienyl, furanyl, pyridyl,thiazolyl, tetrazolyl and quinolinyl; naphthyl; benzhydryl; or benzyl;wherein each heteroaryl, the naphthyl group and each phenyl moiety ofbenzyl and benzhydryl may be substituted by C₁₋₆ alkyl, C₁₋₆ alkoxy,halogen or trifluoromethyl; R³ and R⁴ each independently representshydrogen or C₁₋₆ alkyl or R³ and R⁴ together are linked so as to form aC₁₋₃ alkylene chain; R⁵ represents hydrogen, C₁₋₆ alkyl, C₃₋₇cycloalkyl, C₃₋₇ cycloalkylC₁₋₄ alkyl, phenylC₁₋₄ alkyl, CO₂ R^(a),CONR^(a) R^(b), SOR^(a) or SO₂ R^(a), wherein the phenyl moiety may besubstituted by C₁₋₆ alkyl, C₁₋₆ alkoxy, halogen or trifluoromethyl, andR^(a) and R^(b) are as previously defined; X and Y each independentlyrepresents hydrogen, or together form a group ═O; and Z represents abond, O, S, SO, SO₂, NR⁶, or --(CR⁶ R⁶)-- where each R⁶ is hydrogen orC₁₋₆ alkyl;or a pharmaceutically acceptable salt thereof.
 2. A compoundas claimed in claim 1 whereinn is zero, 1, 2 or 3; R represents C₁₋₆alkyl, C₁₋₆ alkoxy, hydroxy, halogen, cyano, trifluoromethyl, SO₂ C₁₋₆alkyl, NR^(a) R^(b), NR^(a) COR^(b), or CONR^(a) R^(b), where R^(a) andR^(b) each independently represent hydrogen, C₁₋₆ alkyl, phenyl ortrifluoromethyl; R¹ represents phenyl optionally substituted by 1, 2 or3 groups selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇cycloalkyl, C₃₋₇ cycloalkylC₁₋₄ alkyl, --O(CH₂)_(p) O-- where p is 1 or2, halogen, cyano, nitro, trifluoromethyl, trimethylsilyl, OR^(a),SR^(a), SOR^(a), SO₂ R^(a), NR^(a) R^(b), NR^(a) COR^(b), NR^(a) CO₂R^(b), COR^(a), CO₂ R^(a) or CONR^(a) R^(b), where R^(a) and R^(b) areas previously defined; R₂ represents phenyl optionally substituted by 1,2 or 3 groups selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇cycloalkyl, C₃₋₇ cycloalkylC₁₋₄ alkyl, --O(CH₂)_(p) O-- where p is 1 or2, halogen, cyano, nitro, trifluoromethyl, trimethylsilyl, OR^(a),SR^(a), SOR^(a), SO₂ R^(a), NR^(a) R^(b), NR^(a) COR^(b), NR^(a) CO₂R^(b), COR^(a), CO₂ R^(a) or CONR^(a) R^(b), where R^(a) and R^(b) areas previously defined; heteroaryl selected from indazolyl, thienyl,furanyl, pyridyl, thiazolyl, tetrazolyl and quinolinyl; naphthyl;benzhydryl; or benzyl; wherein each heteroaryl, the naphthyl group andeach phenyl moiety of benzyl and benzhydryl may be substituted by C₁₋₆alkyl, C₁₋₆ alkoxy, halogen or trifluoromethyl; R³ and R⁴ eachindependently represents hydrogen or C₁₋₆ alkyl; R⁵ represents hydrogen,C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkylC₁₋₄ alkyl, phenylC₁₋₄alkyl, CO₂ R^(a), CONR^(a) R^(b), SOR^(a) or SO₂ R^(a), wherein thephenyl moiety may be substituted by C₁₋₆ alkyl, C₁₋₆ alkoxy, halogen ortrifluoromethyl, and R^(a) and R^(b) are as previously defined; X and Yeach independently represents hydrogen, or together form a group ═O; andZ represents O, S, or NR⁶, where R⁶ is hydrogen or C₁₋₆ alkyl;or apharmaceutically acceptable salt thereof.
 3. A compound as claimed inclaim 1 of the formula (Ia): ##STR10## wherein X and Y are as defined inclaim 1;Z' is O, S or --CH₂ --; R²⁰ and R²¹ independently representhydrogen, C₁₋₆ alkyl, halogen, trifluoromethyl, OR^(a), or NR^(a) R^(b),where R^(a) and R^(b) are as defined in claim 1; and R²² and R²³independently represent hydrogen or halogen;or a pharmaceuticallyacceptable salt thereof.
 4. A compound as claimed in claim 1 of theformula (Ib): ##STR11## wherein Z" is O or --CH₂ --;R²⁴ and R²⁵independently represent hydrogen or chlorine; and R²⁶ and R²⁷independently represent hydrogen or chlorine, with the proviso that atleast one of R²⁶ and R²⁷ represents chlorine;or a pharmaceuticallyacceptable salt thereof.
 5. A compound as claimed in claim 1 wherein nis zero.
 6. A compound as claimed in claim 1 wherein R¹ representsunsubstituted phenyl or phenyl substituted by one or two groups selectedfrom C₁₋₆ alkyl, halogen and trifluoromethyl.
 7. A claim as claimed inclaim 6 wherein R¹ represents disubstituted phenyl.
 8. A compound asclaimed in claim 1 wherein R² represents unsubstituted or substitutedphenyl, thienyl, furanyl, pyridyl, quinolinyl, naphthyl, or benzhydryl.9. A compound as claimed in claim 8 wherein R² represents unsubstitutedphenyl or phenyl substituted by one or two groups selected fromchlorine, fluorine, methyl, trifluoromethyl, methoxy and dimethylamino.10. A compound as claimed in claim 1 wherein R³ and R⁴ eachindependently represent hydrogen.
 11. A compound as claimed in claim 1wherein R⁵ represents the group SO₂ R^(a) where R^(a) is as defined inclaim
 1. 12. A compound as claimed in claim 11 wherein R⁵ represents SO₂CH₃.
 13. A compound as claimed in claim 1 wherein Z is an oxygen atom.14. A compound as claimed in claim 1 wherein Z is --CH₂ --.
 15. Acompound selected from:N-1-methanesulphonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-(3,4-dichlorobenzamido)propionamide;N-1-methanesulphonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-(3-pyridylcarboxamido)propionamide;N-1-methanesulphonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-(2-chlorobenzamido)propionamide;N-1-methanesulphonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-(3-chlorobenzamido)propionamide;N-1-methanesulphonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-(4-chlorobenzamido)propionamide;N-1-methanesulphonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-(2,6-dichlorobenzamido)propionamide;N-1-methanesulphonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-(3,5-dichlorobenzamido)propionamide;N-1-methanesulphonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-(2,5-dichlorobenzamido)propionamide;N-1-methanesulphonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-(2,4-dichlorobenzamido)propionamide;N-1-methanesulphonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-(2,3-dichlorobenzamido)propionamide;N-1-methanesulphonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-(3,4-dimethoxybenzamido)propionamide;N-1-methanesulphonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-benzamidopropionamide;N-1-methanesulphonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-(3-(2-propyloxy)benzamido)propionamide;N-1-methanesulphonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-(1-naphthyl)carboxamido)!propionamide; N-1-methanesulphonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-(2-naphthyl)carboxamido)!propionamide; N-1-methanesulphonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-(phenylacetamido)propionamide;N-1-methanesulphonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-(3,4-dichlorophenylacetamido)propionamide;N-1-methanesulphonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-(3,5-bis(trifluoromethyl)phenyl)acetamido!propionamide; N-1-methanesulphonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-(diphenylacetamido)propionamide;N-1-methanesulphonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-(4-pyridylcarboxamido)propionamide;N-1-methanesulphonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-(2-pyridylcarboxamido)propionamide;N-1-methanesulphonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-(8-quinolinylcarboxamido)propionamide;ora pharmaceutically acceptable salt thereof.
 16. A compound selectedfrom:N-1-methanesulphonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-(3,4-dichlorobenzylamino)propionamide;N-1-methanesulphonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-(2-methylbenzylamine)propionamide;N-1-methanesulphonylspiro(3H-indole-3,4'-piperidin)-1-yl!-2-benzylamino-3-benzyloxypropionamide;N-1-methanesulphonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-(2-chlorobenzylamino)propionamide;N-1-methanesulphonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-(3-chlorobenzylamino)propionamide;N-1-methanesulphonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-(4-chlorobenzylamino)propionamide;N-1-methanesulphonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-(3-bromobenzylamino)propionamide;N-1-methanesulphonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-(3-fluorobenzylamino)propionamide;N-1-methanesulphonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-(3-cyanobenzylamino)propionamide;N-1-methanesulphonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-(3-nitrobenzylamino)propionamide;N-1-methanesulphonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-(3-methylbenzylamino)propionamide;N-1-methanesulphonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-(3-methoxybenzylamino)propionamide;N-1-methanesulphonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-(4-methoxybenzylamino)propionamide;N-1-methanesulphonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-(4-(dimethylamino)benzylamino)propionamide;N-1-methanesulphonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-(2,4-dichlorobenzylamino)propionamide;N-1-methanesulphonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-(3,5-dichlorobenzylamino)propionamide;N-1-methanesulphonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-(2,3-dichlorobenzylamino)propionamide;N-1-methanesulphonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-(2,6-dichlorobenzylamino)propionamide;N-1-methanesulphonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-(3,5-dimethoxybenzylamino)propionamide;N-1-methanesulphonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-(3-chloro-5-methoxybenzylamino)propionamide;N-1-methanesulphonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-(3,4-dimethoxybenzylamino)propionamide;N-1-methanesulphonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-(3,4-methylenedioxybenzylamino)propionamide;N-1-methanesulphonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-(1-naphthylmethylamino)propionamide;N-1-methanesulphonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-(2-naphthylmethylamino)propionamide;N-1-methanesulphonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-(2-pyridylmethylamino)propionamide;N-1-methanesulphonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-(3-pyridylmethylamino)propionamide;N-1-methanesulphonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-(4-pyridylmethylamino)propionamide;N-1-methanesulphonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-(2-furylmethylamino)propionamide;N-1-methanesulphonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-(5-methylfur-2-yl)methylamino!propionamide; N-1-methanesulphonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-(3-methylthiophen-2-yl)methylamino!propionamide; N-1-methanesulphonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-(5-methylthiophen-2-yl)methylamino!propionamide; N-1-methanesulphonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-benzyloxy-2-(N-(3,4-dichlorobenzyl)-N-(methyl)amino)propionamide;N-1-methanesulphonylspiro(3H-indole-3,4'-piperidin)-1-yl!-2-benzylamino-3-(2-chlorobenzyloxy)propionamide;N-1-methanesulphonylspiro(3H-indole-3,4'-piperidin)-1-yl!-2-benzylamino-3-(3-chlorobenzyloxy)propionamide;N-1-methanesulphonylspiro(3H-indole-3,4'-piperidin)-1-yl!-2-benzylamino-3-(4-chlorobenzyloxy)propionamide;N-1-methanesulphonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-(2-chlorobenzyloxy)-2-(3,4-dichlorobenzylamino)propionamide;N-1-methanesulphonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-(3-chlorobenzyloxy)-2-(3,4-dichlorobenzylamino)propionamide;N-1-methanesulphonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-(4-chlorobenzyloxy)-2-(3,4-dichlorobenzylamino)propionamide;N-1-methanesulphonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-(benzylthio)-2-(3,4-dichlorobenzylamino)propionamide;N-1-methanesulphonylspiro(3H-indole-3,4'-piperidin)-1-yl!-2-benzylamino-3-(3,4-dichlorobenzyloxy)propionamide;N-1-methanesulphonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-(3,4-dichlorobenzyloxy)-2-(3,4-dichlorobenzylamino)propionamide;ora pharmaceutically acceptable salt thereof.
 17. A compound selectedfrom:N-1-methanesulfonylspiro(3H-indole-3,4'-piperidin)-1-yl!-2-(benzylamino)-3-(napth-2-yl)methoxy!propionamide; N-1-methanesulfonylspiro(3H-indole-3,4'-piperidin)-1-yl!-2-(benzylamino)-3-(napth-1-yl)methoxy!propionamide; N-1-methanesulfonylspiro(3H-indole-3,4'-piperidin)-1-yl!-2-N-(methyl)benzylamino!-3-(3,4-dichlorobenzyloxy)propionamide; N-1-methanesulfonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-(3,4-dichlorobenzyloxy)-2-(dimethyl)aminopropionamide;N-1-methanesulfonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-(3,4-dichlorobenzylthio)-2-(benzylamino)propionamide;N-1-methanesulfonylspiro(3H-indole-3,4'-piperidin)-1-yl!-3-(3,4-dichlorobenzylsulfonyl)-2-(benzylamino)propionamide;N-1-methanesulfonylspiro(3H-indole-3,4'-piperidin)-1-yl!-2,3-bis(benzylamino)propionamide;N-1-methanesulfonylspiro(3H-indole-3,4'-piperidin)-1-yl!-2-(benzylamino)-3-(3,4-dichlorobenzylamino)propionamide;N-1-methanesulfonylspiro(3H-indole-3,4'-piperidin)-1-yl!-2-(benzylamino)-3-(N-methyl-3,4-dichlorobenzylamino)propionamide;N-1-methanesulfonylspiro(3H-indole-3,4'-piperidin)-1-yl!-2-(benzylamino)-5-phenylpentanamide;N-1-methanesulfonylspiro(3H-indole-3,4'-piperidin)-1-yl!-2-(benzylamino)-5-(3,4-dichlorophenyl)pentanamide;N-1-methanesulfonylspiro(3H-indole-3,4'-piperidin)-1-yl!-2-(benzylamino)-5-(3,4-dichlorophenyl)butanamide;ora pharmaceutically acceptable salt thereof.
 18. A compound selectedfrom:N-1-methanesulfonylspiro(3H-indole-3,4'-piperidin)-1-yl!-2-(benzylamino)-3-(3,4-dichlorobenzyloxy)propionamide;N-1-methanesulfonylspiro(3H-indole-3,4'-piperidin)-1-yl!-2-(3,4-dichlorobenzylamino)-3-(3,4-dichlorobenzyloxy)propionamide;ora pharmaceutically acceptable salt thereof.
 19. A pharmaceuticalcomposition comprising a compound as claimed in claim 1 in associationwith a pharmaceutically acceptable carrier or excipient.
 20. A methodfor the treatment of physiological disorders associated with an excessof tachykinins, which method comprises administration to a patient inneed thereof of a tachykinin reducing amount of a compound according toclaim 1, or a pharmaceutically acceptable salt thereof.
 21. A method forthe treatment or prevention of pain or inflammation, which methodcomprises administration to a patient in need thereof a tachykininreducing amount of a compound according to claim 1, or a pharmaceuticalsalt thereof.
 22. A method for the treatment or prevention of migraine,which method comprises administration to a patient in need thereof atachykinin reducing amount of a compound according to claim 1, or apharmaceutical salt thereof.
 23. A method for the treatment orprevention of emesis, which method comprises administration to a patientin need thereof a tachykinin reducing amount of a compound according toclaim 1, or a pharmaceutical salt thereof.
 24. A method according toclaim 20 for the treatment of postherpetic neuralgia.
 25. A process forthe preparation of a compound of claim 1, which comprises:(A), where Xand Y are both hydrogen, reacting a compound of formula (II): ##STR12##wherein R, R¹, R³, R⁴, R⁵, Z and n are as defined in claim 1, with analdehyde of formula R² --CHO in the presence of a reducing agent; or(B), where X and Y together form a group ═O, may be prepared by thereaction of a compound of formula (II) with an acyl halide of formula R²--COHal where Hal is a halogen atom; or (C) by the reaction of acompound of formula (III) with a piperidinyl derivative of formula (IV):##STR13## wherein R, R¹, R², R³, R⁴, R⁵, X, Y, Z and n are as defined inclaim 1 with the proviso that R⁵ is not hydrogen; each process beingfollowed, where necessary, by the removal of any protecting group wherepresent; and when the compound of formula (I) is obtained as a mixtureof enantiomers or diastereoisomers, optionally resolving the mixture toobtain the desired enantiomer; and/or, if desired, converting theresulting compound of formula (I) or a salt thereof, into apharmaceutically acceptable salt thereof.